CYP450 Genes

Pharmacogenetics of second-generation antipsychotics.

http://www.ncbi.nlm.nih.gov/pubmed/24897292 [20]

Pharmacogene Variation Consortium

https://www.pharmvar.org/

PharmGKB The Pharmacogenomics Knowledgebase.

https://www.pharmgkb.org/ [248]

Clinical applications of CYP genotyping in psychiatry.

http://www.ncbi.nlm.nih.gov/pubmed/25200585 [249]

Meta-analysis of genetic polymorphisms on CYP1A2 activity

https://www.ncbi.nlm.nih.gov/pubmed/29282363 [286]

Single nucleotide polymorphisms and haplotypes of CYP1A2 in a Japanese population.

https://www.ncbi.nlm.nih.gov/pubmed/15770072 [287]

“In order to identify genetic polymorphisms and haplotype frequencies of CYP1A2 in a Japanese population, the enhancer and promoter regions, all the exons with their surrounding introns, and intron 1

were sequenced from genomic DNA from 250 Japanese subjects. Thirty-three polymorphisms were found, including 13 novel ones: 2 in the enhancer region, 5 in the exons, and 6 in the introns. The most

common single nucleotide polymorphism (SNP) was -163C>A (CYP1A2*1F allele) with a 0.628 frequency. In addition to six previously reported non-synonymous SNPs, three novel ones, 125C>G

(P42R, CYP1A2*15 allele, MPJ6_1A2032), 1130G>A (R377Q, *16 allele, MPJ6_1A2033), and 1367G>A (R456H, *8 allele, MPJ6_1A2019), were found with frequencies of 0.002, 0.002, and 0.004,

respectively. No polymorphism was found in the known nuclear transcriptional factor-binding sites in the enhancer region. Based on linkage disequilibrium analysis, the CYP1A2 gene was analyzed as one

haplotype block. Using the 33 detected polymorphisms, 14 haplotypes were unambiguously identified, and 17 haplotypes were inferred by aid of an expectation-maximization-based program. Among them,

the second major haplotype CYP1A2*1L is composed of -3860G>A (*1C allele), -2467delT (*1D allele), and -163C>A (*1F allele). Network analysis suggested that relatively rare haplotypes were derived from

three major haplotypes, *1A, *1M, and *1N in most cases. Our findings provide fundamental and useful information for genotyping CYP1A2 in the Japanese, and probably Asian populations.”[287]

Influence of genetic polymorphisms, smoking, gender and age on CYP1A2 activity in a Turkish population.

https://www.ncbi.nlm.nih.gov/pubmed/15770072[281]

“The 17X:137X ratios were increased in smokers (p < 0.0001) and tended to be higher in men both among nonsmokers (p = 0.051) and smokers (p = 0.064). Age-related differences were observed only

among nonsmoking women (p = 0.024). The -163C>A polymorphism correlated with 17X:137X ratios only in smokers (p = 0.006). Furthermore, increased 17X:137X ratios were observed in CYP1A2

haplotype H4 (-3860G, -3113G, -2467del, -739T, -729C, -163A and 5347T) carriers in the overall study population (p = 0.026). Multiple regression analyses including smoking, gender, -163C>A genotype and

age revealed a significant influence of smoking (p < 0.0001) and gender (p = 0.002) in the overall study population. However, in nonsmokers only the influence of gender remained significant (p = 0.021), while

in smokers the influence of the -163C>A genotype held the statistical significance (p = 0.019). The influence of haplotype H4 remained significant (p = 0.028) in the overall study population in similar

analyses.”[281]

Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects.

http://www.ncbi.nlm.nih.gov/pubmed/23089672 [250]

There is a large amount of variability in psychotropic drug response and variations in CYP450 genes, including CYP1A2, which may affect this variability. There are several articles, which review the relevant

clinical implications of altered CYP1A2 metabolism. [20, 247-250] 

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver.

http://www.ncbi.nlm.nih.gov/pubmed/20538623 [252]

“To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and

enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes

enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme

activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis41 regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450

activity.” [252]

CYP450 pharmacogenetic treatment strategies for antipsychotics: a review of the evidence.

http://www.ncbi.nlm.nih.gov/pubmed/23870808 [258]

“CYP2D6, CYP1A2, and CYP3A4/5 are major enzymes in the metabolism of antipsychotics and polymorphisms of alleles for these proteins are associated with altered plasma levels… Numerous

studies have shown a significant association between genotype and adverse effects, such as CYP2D6 polymorphisms and tardive dyskinesia. This review summarizes evidence for the role of CYP450

genetic variants in the response to antipsychotic medications and the clinical implications of pharmacogenetics in the management of patients with schizophrenia.” [258]

Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2.

http://www.ncbi.nlm.nih.gov/pubmed/19590965 [259]

“To date, more than 15 variant alleles and a series of sub-variants of the CYP1A2 gene have been identified and some of them have been associated with altered drug clearance and response to drug

therapy. For example, lack of response to clozapine therapy due to low plasma drug levels has been reported in smokers harboring the -163A/A genotype; there is an association between CYP1A2*1F (-

163C>A) allele and the risk for leflunomide-induced host toxicity. The *1F allele is associated with increased enzyme induction whereas *1C causes reduced induction. Further studies are warranted to

explore the clinical and toxicological significance of altered CYP1A2 expression and activity caused by genetic, epigenetic, and environmental factors.” [259]

CYP1A2 is more variable than previously thought: a genomic biography of the gene behind the human drug-metabolizing enzyme.

http://www.ncbi.nlm.nih.gov/pubmed/20881513 [260]

“As human genetic diversity has been reported to decrease with distance from Ethiopia, we resequenced CYP1A2 in five Ethiopian ethnic groups representing a rough northeast to southwest

transect across… We found 49 different variable sites (30 of which are novel), nine nonsynonymous changes (seven of which are novel), one synonymous change and 55 different haplotypes, only three of

which are previously reported.” [260]

The dosing of atypical antipsychotics.

http://www.ncbi.nlm.nih.gov/pubmed/15883149 [261]

“Dosage alterations of …quetiapine, dependent on cytochrome P450 3A (CYP3A), may be necessary when used with other drugs that inhibit or induce their metabolic enzymes. Genetic variations of

cytochrome P450 2D6 (CYP2D6) and drug-drug interactions causing inhibition (CYP2D6 and/or CYP3A) or induction (CYP3A) may be important for risperidone, and perhaps for aripiprazole, dosing.

Adding inhibitors may cause side effects more easily in drugs with a narrow therapeutic window, such as clozapine or risperidone, than in those with a wide therapeutic window, such as olanzapine or

aripiprazole. Adding inducers may be associated with a gradual development of lost efficacy.” [261] 

Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms.

http://www.ncbi.nlm.nih.gov/pubmed/18466106 [262]

“CYP1A2 is involved in the metabolism of several widely used drugs and endogenous compounds, and in the activation of pro-carcinogens. Both genetic and environmental factors influence the activity of this enzyme. The current knowledge regarding factors influencing the activity of CYP1A2 is summarized in this review…The functional significance and clinical importance of CYP1A2 gene polymorphisms are reviewed and interethnic differences in the distribution of CYP1A2 variant alleles and haplotypes are summarized. Finally, future perspectives for the possible clinical applications of CYP1A2 genotyping are discussed.” [262]

A theoretical study on the mechanism of a superficial mutation inhibiting the enzymatic activity of CYP1A2.

http://www.ncbi.nlm.nih.gov/pubmed/24464701 [263]

“CYP1A2, one of the major members of cytochrome P450 in human liver, participates in the metabolism of various drugs. While most harmful mutations are located near the catalytic core of CYP1A2, a

recently found loss-of-function mutation, F186L, is on the surface… Based on these findings, a detailed mechanism of how F186 regulates the functions of CYP1A2 was proposed, and it may shed light on the diverse effects of SNPs and the personalized drug design.” [263]

Six novel nonsynonymous CYP1A2 gene polymorphisms: catalytic activities of the naturally occurring variant enzymes.

http://www.ncbi.nlm.nih.gov/pubmed/14563787 [264]

“Six novel nonsynonymous nucleotide alterations were found in the cytochrome P450 1A2 gene in a Japanese population, which resulted in the following amino acid substitutions: T83M, E168Q, F186L,

S212C, G299A, and T438I… Kinetic analyses performed for the ethoxyresorufin O-deethylation revealed that the Vmax of the F186L (*11) variant was approximately 5% of that of the CYP1A2 wild

type, despite a 5-fold lower Km value of the variant, the consequence of which was reduced enzymatic activity toward the substrate. Thus, for the first time, phenylalanine at residue 186 is suggested to be a

critical amino acid for catalytic activity.” [264] 

Association between CYP1A2 polymorphisms and clozapine-induced adverse reaction in patients with schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/22901441 [265]

“CYP1A2 *1F contains a 163 C4A transition in intron 1, which influences the gene’s induction affecting the magnitude of increase of caffeine metabolism after smoking…CYP1A2 alleles *1C, *1D and *1F are

all due to mutations in the regulatory regions of the gene and at least for CYP1A2 *1C and *1F, the functional effects associated with their presence have been adequately characterized. CYP1A2 *1C

contains a 3860 G>A transition in the flanking region of the gene, causing a decrease in induction. CYP1A2 *1F contains a 163 C>A transition in intron 1, which influences gene induction affecting the

magnitude of increase of caffeine metabolism after smoking…Patients with ADRs had a higher frequency of CYP1A2 low activity allele combinations (8/12; 67%) and lower CYP1A2-mRNA levels than

patients without ADRs (6/22; 27%, P = 0.019).” [265]

Impact of CYP1A2 and CYP2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients.

http://www.ncbi.nlm.nih.gov/pubmed/17503978 [266]

“Clozapine and N-desmethylclozapine concentration-to-dose (C/D) ratios were significantly higher in patients carrying 2 CYP1A2 single nucleotide polymorphisms (SNPs), previously suggested to cause

low enzyme activity, compared to those with no such SNPs (p < .05)… CYP1A2 variants *1C and *1D seem to be associated with higher serum clozapine concentrations and an increased risk of developing

insulin and lipid elevations and insulin resistance on a given dose of clozapine.” [266] 

Influence of the genetic polymorphism in the 5'-noncoding region of the CYP1A2 gene on CYP1A2 phenotype and urinary mutagenicity in smokers.

http://www.ncbi.nlm.nih.gov/pubmed/16188490 [267]

“The functional significance of genetic polymorphisms on tobacco smoke-induced CYP1A2 activity was examined…Heavy smokers (n=48, with urinary nicotine plus its metabolites>or=0.69 mg/mmol

creatinine) with variant allele -2467delT or -163A had significantly increased urinary mutagenicity (p<0.01 and <0.05). CYP1A2 genetic polymorphisms are shown to influence the CYP1A2 phenotype in

smokers, -2467 T–>Del T having the main effect. This information is of interest for future studies assessing the possible role of tobacco smoke-inducible CYP1A2 genotypes as individual susceptibility

factors in exposure to carcinogens.” [267] 

CYP1A2 genetic polymorphisms are associated with early antidepressant escitalopram metabolism and adverse reactions.

http://www.ncbi.nlm.nih.gov/pubmed/23859573 [268]

“The liver CYP1A2 enzyme may metabolize antidepressant escitalopram (S-CIT) to Sdesmethylcitalopram (S-DCIT) and S-didesmethylcitalopram (S-DDCIT). This study tested whether genetic polymorphisms in the CYP1A2 gene are associated with the treatment responses to SCIT… CYP1A2 SNPs rs2069521, rs2069526, rs4646425 and rs4646427 are significantly associated with the metabolic ratios of S-DDCIT/S-DCIT (p = 0.002, 0.018, 0.008 and 0.004, respectively) at week 2 of treatment. Carriers of the allele types associated with higher S-DDCIT/S-DCIT ratios had more severe side effects…These results suggest that genetic variants in CYP1A2 may be indicators for S-CIT metabolism and that the fast metabolizers may experience more severe adverse reactions in the early stages of S-CIT treatment.” [268]

Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome.

http://www.ncbi.nlm.nih.gov/pubmed/19636338 [164]

“In our study population, CYP1A2*1F/*1F genotype alone resulted in a 22% reduction of dose-/body weight-normalized olanzapine serum concentrations compared to homo- and heterozygote carriers of

CYP1A2*1A (both groups without inducers). This effect was independent of the well-known effect of nducing agents (here tobacco smoke and carbamazepine which led to on average 28% lower

concentrations in CYP1A2*1A carriers and 26% lower concentrations in CYP1A2*1F/*1F carriers). Consistently, patients with the CYP1A2*1F/*1F genotype taking inducers had 22% lower concentrations

compared to CYP1A2*1A carriers taking inducers. The influence of genotype alone remained significant after Bonferroni's post hoc test.” [164] 

Genetics of caffeine consumption and responses to caffeine.

http://www.ncbi.nlm.nih.gov/pubmed/20532872 [269]

“Modeling based on twin studies reveals that genetics plays a role in individual variability in caffeine consumption and in the direct effects of caffeine. Both pharmacodynamic and pharmacokinetic

polymorphisms have been linked to variation in response to caffeine… A single nucleotide C→A polymorphism at position 734 within intron 1 (rs762551) is correlated with high induction of the P-450

1A2 enzyme in Caucasian subjects. Smoking subjects with A/A genotype metabolize caffeine at 1.6 times the rate of the other genotypes, while no significant differences are found for nonsmoking

subjects. The genetic polymorphism therefore modifies environmental impact on enzyme activity.” [269]

Inducibility of CYP1A2 by omeprazole in vivo related to the genetic polymorphism of CYP1A2.

http://www.ncbi.nlm.nih.gov/pubmed/12445035 [270]

“Mutations of CYP2C19 and CYP1A2 were identified by PCR-RFLP. Omeprazole, 120 mg day-1, was given to 12 extensive metabolizers (EM) with respect to CYP2C19 (six CYP1A2*1F/CYP1A2*1F and six

CYP1A2*1C/CYP1A2*1F of CYP1A2) for 7 days. CYP1A2 activity was determined on three occasions, namely on day 1, day 9 and day 16 using the caffeine plasma index (the ratio of the concentrations of

paraxanthine to caffeine), 6 h after oral administration of 200 mg caffeine… There was a significant difference (P = 0.002) between the caffeine ratios for CYP1A2*1F/CYP1A2*1F and CYP1A2*1C/CYP1A2*1F  genotypes on day 9, but not on day 1 or day 16 (P > 0.05). The changes in the ratios from day 9 to day 1 (48% +/- 20%vs 19% +/- 20%) and from day 9 to day 16 (50% +/- 31%vs

15% +/- 22%) were significantly different (P < 0.05) between the CYP1A2*1F/CYP1A2*1F and CYP1A2*1C/CYP1A2*1F genotypes… The CYP1A2*1C and CYP1A2*1F genetic polymorphisms influenced the induction of CYP1A2 activity in vivo by omeprazole.” [270]

CYP1A2, GSTM1, and GSTT1 polymorphisms and diet effects on CYP1A2 activity in a crossover feeding trial.

http://www.ncbi.nlm.nih.gov/pubmed/19843669 [271]

“Using a randomized, crossover feeding trial in humans, we investigated the dose effects of cruciferous vegetables and the effects of any interaction between cruciferous and apiaceous vegetables on

CYP1A2 activity. We also investigated whether response varied by CYP1A2*1F, GSTM1, and GSTT1 genotypes (glutathione S-transferases that metabolize crucifer constituents) and whether CYP1A2

activity rebounds after apiaceous vegetables are removed from the diet… These results suggest complex interactions among dietary patterns, genetic variation, and modulation of biotransformation that

may not be apparent in observational studies.” [271] 

Duloxetine: clinical pharmacokinetics and drug interactions.

http://www.ncbi.nlm.nih.gov/pubmed/21366359 [272]

“Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal

function… Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a

clinically significant degree… Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C(max) of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or

in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment.” [272] 

Genomics and pharmacogenomics of schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/20718829 [273]

“Schizophrenia (SCZ) is among the most disabling of mental disorders…SCZ has a heritability estimated at 60-90%. Genetic studies in SCZ have revealed the presence of chromosome anomalies,

copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single nucleotide polymorphisms (SNPs) in microRNA genes, mitochondrial

DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the

positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major

substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and

95% of CYP3A4. About 10-20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the tri-genic cluster integrated by

the CYP2D6+CYP2C19+CYP2C9 genes. The pharmacogenomic response of SCZ patients to conventional psychotropic drugs also depends on genetic variants associated with SCZ-related genes.

Consequently, the incorporation of pharmacogenomic procedures both to drugs in development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system

(CNS) disorders.” [273]

Pharmacogenomics can improve antipsychotic treatment in schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/23606027 [274]

“Schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population, and heritability of up to 80%. Drug therapy is an important approach to treating the disease. However, the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects. Many studies have indicated that nearly 30% of patients exhibit little or no improvements associated with 

antipsychotics. The response of individual patients who are given the same dose of the same drug varies considerably. In addition, antipsychotic drugs are often accompanied by adverse drug reactions (ADRs), which can cause considerable financial loss in addition to the obvious societal harm… In this review, we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes (CYP2D6, CYP1A2, CYP3A4, etc.), drug transporters (mainly ABCB1) and neurotransmitter receptors (dopamine receptors and serotonin receptors, etc.). We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications.” [274]

The CYP1A2 -163C>A polymorphism is associated with clozapine-induced generalized tonic-clonic seizures in Brazilian schizophrenia patients.

http://www.ncbi.nlm.nih.gov/pubmed/23601795 [275]

“We evaluated two polymorphisms at CYP1A2 (*1C and *1F) in a sample of 108 European-derived patients with schizophrenia and their influence on the pro-convulsive effect of clozapine. We found the

*1F/*1F genotype to be significantly associated with seizures, and no relationship was observed with combinations of *1F and *1C alleles.” [275]

Clinically significant drug interactions with atypical antipsychotics.

http://www.ncbi.nlm.nih.gov/pubmed/24170642 [276]

“Atypical antipsychotics [also known as second-generation antipsychotics (SGAs)] have become a mainstay therapeutic treatment intervention for patients with schizophrenia, bipolar disorders and other

psychotic conditions. … Smoking is very common among psychiatric patients and can induce CYP1A2 enzymes, thereby lowering expected plasma levels of certain SGAs. It is recommended that ziprasidone and lurasidone are taken with food to promote drug absorption, otherwise their bioavailability can be reduced. Clinicians must be aware of the variety of factors that can increase the likelihood of clinically significant drug interactions with SGAs, and must carefully monitor patients to maximize treatment efficacy while minimizing adverse events.” [276]

Cost-effectiveness of one-time genetic testing to minimize lifetime adverse drug reactions.

http://www.ncbi.nlm.nih.gov/pubmed/25987241 [288]

“We evaluated the cost-effectiveness of one-time pharmacogenomic testing for preventing adverse drug reactions (ADRs) over a patient's lifetime. We developed a Markov-based Monte Carlo microsimulation model to represent the ADR events in the lifetime of each patient. The base-case considered a 40-yearold patient. We measured health outcomes in life years (LYs) and quality-adjusted LYs (QALYs) and estimated costs using 2013 US$. In the base-case, one-time genetic testing had an incremental cost effectiveness ratio (ICER) of $43,165 (95% confidence interval (CI) is ($42, 769, $43,561)) per additional LY and $53,680 per additional QALY (95% CI is ($53, 182, $54,179)), hence under the base-case onetime genetic testing is cost-effective. The ICER values were most sensitive to the average probability of death due to ADR, reduction in ADR rate due to genetic testing, mean ADR rate and cost of genetic testing.” [288]

Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.

https://www.ncbi.nlm.nih.gov/pubmed/24160757 [277]

“Exogenous cannabinoids are structurally and pharmacologically diverse compounds that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for

these compounds to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clinical care and drug interactions…

However, the absence of interaction between CBD from oromucosal cannabis extract with omeprazole suggests a less significant role of CYP2C19 in CBD metabolism. Studies of THC, CBD, and CBN

inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clinically significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb

(marijuana) likely induces CYP1A2 mediated theophylline metabolism, although the role of cannabinoids specifically in eliciting this effect is questionable.” [277]

Cruciferous vegetable consumption alters the metabolism of the dietary carcinogen 2-amino-1-methyl-6- phenylimidazo [4, 5-b] pyridine (PhIP) in humans.

https://www.ncbi.nlm.nih.gov/pubmed/15073045 [278]

“Consumption of red meat is associated with an increased risk of colorectal cancer, whereas cruciferous vegetable consumption reduces cancer risk. While the mechanisms remain to be determined,

cruciferous vegetables may act by altering the metabolism of carcinogens present in cooked food, such as the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP). The aim of this

study was to evaluate the effect of cruciferous vegetable consumption on the metabolism of PhIP in 20 non-smoking Caucasian male subjects…While the urinary excretion of both PhIP metabolites accounted for approximately 39% of the PhIP dose in phases 1 and 3, they accounted for approximately 49% of the dose in phase 2. This study demonstrates that cruciferous vegetable consumption can induce both the phase I and II metabolism of PhIP in humans.” [278] 

Genetic polymorphism analysis of the drug-metabolizing enzyme CYP1A2 in a Uyghur Chinese population: a pilot study.

https://www.ncbi.nlm.nih.gov/pubmed/26383175 [279]

“CYP1A2 is a highly polymorphic gene and CYP1A2 enzyme results in broad inter-individual variability in response to certain pharmacotherapies, while little is known about the genetic variation of CYP1A2 in Uyghur Chinese population. The aim of the present study was to screen Uyghur volunteers for CYP1A2 genetic polymorphisms. 2. We used DNA sequencing to investigate promoter, exons, introns, and 3'

UTR of the CYP1A2 gene in 96 unrelated healthy Uyghur individuals. We also used SIFT (Sorting Intolerant from Tolerant) and PolyPhen-2 (Polymorphism Phenotyping v2) to predict the protein function

of the novel non-synonymous mutation in CYP1A2 coding regions. 3. We identified 20 different CYP1A2 polymorphisms in the Uyghur Chinese population, including two novel variants (119A > G and

2410G > A). Variant 119A > G was predicted to be probably damaging on protein function by PolyPhen- 2, by contrast, 2410G > A was identified as benign. The allele frequencies of CYP1A2*1A, *1B, *1F,

*1G, *1J, *1M, *4, and *9 were 23.4%, 53.1%, 3.7%, 2.6%, 2.6%, 13.5%, 0.5%, and 0.5%, respectively. The frequency of *1F, a highly inducible allele, was higher in our sample population compared with that

in the Caucasian population (p < 0.05). The most common genotype combinations were *1A/*1B (46.9%) and *1B/*1M (27.1%). 4. Our results provide basic information on CYP1A2 polymorphisms in

Uyghur individuals and suggest that the enzymatic activities of CYP1A2 may differ among the diverse ethnic populations of the world.” [279]

Pharmacogenetics of CYP1A2 activity and inducibility in smokers and exsmokers.

https://www.ncbi.nlm.nih.gov/pubmed/23492909 [280]

“There is a high interindividual variability in cytochrome P4501A2 (CYP1A2) activity and in its inducibility by smoking, only poorly explained by known CYP1A2 polymorphisms. We aimed to study the

contribution of other regulatory pathways, including transcription factors and nuclear receptors, toward this variability. CYP1A2 activity was determined by the paraxanthine/caffeine ratio in 184 smokers and

in 113 of them who were abstinent for 4 weeks. Participants were genotyped for 22 polymorphisms in 46 12 genes. A significant influence on CYP1A2 inducibility was observed for the NR1I3 rs2502815

(P=0.0026), rs4073054 (P=0.029), NR2B1 rs3818740 (P=0.0045), rs3132297 (P=0.036), AhR rs2282885 (P=0.040), rs2066853 (P=0.019), NR1I1 rs2228570 (P=0.037), and NR1I2 rs1523130

(P=0.044) polymorphisms. Among these, the NR1I3 rs2502815 (P=0.0045), rs4073054 (P=0.048), and NR2B1 rs3818740 (P=0.031) also influenced CYP1A2 basal activity. This is the first in-vivo

demonstration of the influence of genes involved in CYP1A2 regulatory pathways on its basal activity and inducibility by smoking. These results need to be confirmed by other studies.” [280]

Influence of genetic polymorphisms, smoking, gender and age on CYP1A2 activity in a Turkish population.

https://www.ncbi.nlm.nih.gov/pubmed/19450128 [281]

“Smoking has the strongest impact on CYP1A2 activity, while gender and haplotype H4 showed marginal effects. The influence of the -163C>A polymorphism on CYP1A2 activity in smokers suggests an effect on the inducibility of the enzyme.” [281]

 Literature Summary: Cytochrome P450 2B6: (CYP2B6)

Pharmacogene Variation Consortium

https://www.pharmvar.org/

PharmGKB The Pharmacogenomics Knowledgebase.

https://www.pharmgkb.org/ [248]

Clinical applications of CYP genotyping in psychiatry.

http://www.ncbi.nlm.nih.gov/pubmed/25200585 [249]

Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and

endogenous effects.

http://www.ncbi.nlm.nih.gov/pubmed/23089672 [250]

Applications of CYP450 testing in the clinical setting.

http://www.ncbi.nlm.nih.gov/pubmed/23588782 [251]

There is a large amount of variability in psychotropic drug response and variations in CYP450 genes, including CYP2B6, may impact this variability. There are several articles which review the relevant

clinical implications of altered CYP2B6 metabolism. [247-249, 251]

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver.

http://www.ncbi.nlm.nih.gov/pubmed/20538623 [252]

“…we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme

activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways

relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of

SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity.” [252]

Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance.

http://www.ncbi.nlm.nih.gov/pubmed/23467454 [289]

CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme.

http://www.ncbi.nlm.nih.gov/pubmed/18781911 [290]

CYP2B6 is responsible for the metabolism of several medications including bupropion and methadone. This gene is also displays highly variable expression between individuals due to genetic variation,

environmental contributions, and inhibition and induction effects of other co-administered medications and food products. Resent advances in the understanding of this enzyme have made it a potential

therapeutic target. [289, 290] 47

Prevalence of poor and rapid metabolizers of drugs metabolized by CYP2B6 in North Indian population residing in Indian national capital territory.

http://www.ncbi.nlm.nih.gov/pubmed/23961363 [291]

“Identification of poor and rapid metabolizers for the category of drugs metabolized by cytochrome P450 2B6 (CYP2B6) is important for understanding the differences in clinical responses of drugs metabolized by this enzyme… Results indicate that 20.56% individuals in the target population were poor metabolizers for the category of drugs metabolized by CYP2B6. The baseline information would be

clinically useful before administering the drugs metabolized by this isoform.” [291]

Polymorphic variants of cytochrome P450 2B6 (CYP2B6.4–CYP2B6.9) exhibit altered rates of metabolism for bupropion and efavirenz: a charge-reversal mutation in the K139E variant (CYP2B6.8) impairs formation of a functional cytochrome p450-reductase complex.

http://www.ncbi.nlm.nih.gov/pubmed/21659470 [292]

“In this study, metabolism of bupropion, efavirenz, and 7-ethoxy-4-trifluoromethylcoumarin (7-EFC) by CYP2B6 wild type (CYP2B6.1) and six polymorphic variants (CYP2B6.4 to CYP2B6.9) was investigated

in a reconstituted system to gain a better understanding of the effects of the mutations on the catalytic properties of these naturally occurring variants… In this work, we have characterized the catalytic

properties of six polymorphic variants of CYP2B6 (CYP2B6.4 to CYP2B6.9) in a reconstituted system to gain a better understanding of the mechanism by which these genetic mutations affect the catalytic

activities of CYP2B6… Results from this work provide further insights to better understand the genotype-phenotype correlation regarding CYP2B6 polymorphisms and drug metabolism.” [292]

Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver.

http://www.ncbi.nlm.nih.gov/pubmed/11470993 [293]

“In this study, we present the first systematic investigation of genetic polymorphism in the CYP2B6 gene on chromosome 19… A total of nine novel point mutations were identified, of which five result in amino acid substitutions in exon 1 (C64T, Arg22Cys), exon 4 (G516T, Gln172His), exon 5 (C777A, Ser259Arg and A785G, Lys262Arg) and exon 9 (C1459T, Arg487Cys) and four are silent mutations (C78T, G216C, G714A and C732T)… By screening a population of 215 subjects the C64T, G516T, C777A, A785G and C1459T mutations were found at frequencies of 5.3%, 28.6%, 0.5%, 32.6% and 14.0%, respectively.

Haplotype analysis revealed six different mutant alleles termed CYP2B6*2 (C64T), *3 (C777A), *4 (A785G), *5 (C1459T), *6 (G516T and A785G) and *7 (G516T, A785G and C1459T). By analyzing a

large number of human liver samples, significantly reduced CYP2B6 protein expression and Smephenytoin N-demethylase activity were found in carriers of the C1459T (R487C) mutation (alleles *5

and *7). These data demonstrate that the extensive interindividual variability of CYP2B6 expression and function is not only due to regulatory phenomena, but also caused by a common genetic

polymorphism.” [293] 

Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver.

http://www.ncbi.nlm.nih.gov/pubmed/18171905 [294]

“The common allele CYP2B6*6 [c. 516G>T, Q172H, and c.785A>G, K262R] has previously been associated with lower expression in human liver and with increased plasma levels of efavirenz in human

immunodeficiency virus patients, but the molecular mechanism has remained unclear. We present novel data showing that hepatic CYP2B6 mRNA levels are reduced in *6 carriers, suggesting a

pretranslational mechanism resulting in decreased expression.” [294] 

Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro.

http://www.ncbi.nlm.nih.gov/pubmed/17559344 [295]

“We have shown that CYP2B6 genetic polymorphism markedly influences the metabolism of efavirenz in human liver microsomes. Importantly, the CYP2B6*6 allele harboring the SNPs c.516G>T [Q172H]

and c.785A>G [K262R] was significantly associated with a pronounced decrease in CYP2B6 expression and activity, as well as a low rate of efavirenz 8-hydroxylation. These results represent a first step

towards elucidating the mechanism by which this allele identifies patients exhibiting very high efavirenz plasma concentrations.” [295]

CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction.

http://www.ncbi.nlm.nih.gov/pubmed/21790905 [296]

“Adequate methadone dosing in methadone maintenance treatment (MMT) for opioid addiction is critical for therapeutic success. One of the challenges in dose determination is the inter-individual variability in dose-response. Methadone metabolism is attributed primarily to cytochrome P450 enzymes CYP3A4, CYP2B6 and CYP2D6. The CYP2B6*6 allele [single nucleotide polymorphisms (SNPs) 785A>G

(rs2279343) and 516G>T (rs3745274)] was associated with slow methadone metabolism… The results remain significant after controlling for age, sex and the ABCB1 SNP 1236C>T (rs1128503), which was

previously shown to be associated with high methadone dose requirement in this population (P=0.006, 0.030, respectively). An additional 77 CYP2B6, CYP3A4 and CYP2D6 SNPs were genotyped. Of these,

24 SNPs were polymorphic and none showed significant association with methadone dose. Further studies are necessary to replicate these preliminary findings in additional subjects and other

populations.” [296]

Genomics and pharmacogenomics of schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/20718829 [273]

“Schizophrenia (SCZ) is among the most disabling of mental disorders…SCZ has a heritability estimated at 60-90%. Genetic studies in SCZ have revealed the presence of chromosome anomalies,

copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single nucleotide polymorphisms (SNPs) in microRNA genes, mitochondrial

DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the

positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major

substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and

95% of CYP3A4. About 10-20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the tri-genic cluster integrated by

the CYP2D6+CYP2C19+CYP2C9 genes. The pharmacogenomic response of SCZ patients to conventional psychotropic drugs also depends on genetic variants associated with SCZ-related genes.

Consequently, the incorporation of pharmacogenomic procedures both to drugs in development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system

(CNS) disorders.” [273]

Pharmacogenomics study in a Taiwan methadone maintenance cohort.

http://www.ncbi.nlm.nih.gov/pubmed/25278738 [284]

“Pharmacogenomics is research to study the drug treatment responses in subgroups of patients according to their genetic variants or genetic expression information. Methadone maintenance

treatment, which is usually prescribed for patients with heroin dependence, was launched in Taiwan by the government in 2006. In this study, 366 patients who had taken methadone continually in the

previous 7 days were examined. Data from administration of the Treatment Outcomes Profile (TOP), Severity of Dependence Scale (SDS), Clinical Opioid Withdrawal Scale (COWS), and Treatment

Emergent Symptoms Scale (TESS) were obtained from patients' report records. Genes encoding the liver cytochrome P-450 (CYP) enzymes that are involved with the metabolism of methadone (CYP2B6,

3A4 and 2C19) were selected and genotyped in this cohort. We found that the SNPs on CYP2B6 were associated with plasma S-methadone concentration; SNPs on CYP3A4 were associated with

withdrawal symptoms and side effects; and SNPs on CYP2C19 were associated with methadone dose. SNPs in the genes encoding the morphine phase II metabolic enzyme, UGT2B7, were associated with

withdrawal symptom scores. In pharmacodynamic genes, the SNPs on OPRM1 were associated with insomnia and change in libido side effects. We conclude that SNP markers may be useful for future

methadone dosage adjustment and to reduce adverse reactions.” [284]

Cost-effectiveness of one-time genetic testing to minimize lifetime adverse drug reactions.

http://www.ncbi.nlm.nih.gov/pubmed/25987241 [288]

“We evaluated the cost-effectiveness of one-time pharmacogenomic testing for preventing adverse drug reactions (ADRs) over a patient's lifetime. We developed a Markov-based Monte Carlo microsimulation model to represent the ADR events in the lifetime of each patient. The base-case considered a 40-yearold patient. We measured health outcomes in life years (LYs) and quality-adjusted LYs (QALYs) and estimated costs using 2013 US$. In the base-case, one-time genetic testing had an incremental costeffectiveness ratio (ICER) of $43,165 (95% confidence interval (CI) is ($42, 769, $43,561)) per additional LY and $53,680 per additional QALY (95% CI is ($53, 182, $54,179)), hence under the base-case onetime genetic testing is cost-effective. The ICER values were most sensitive to the average probability of death due to ADR, reduction in ADR rate due to genetic testing, mean ADR rate and cost of genetic testing.” [288]

CYP2B6 and bupropion's smoking-cessation pharmacology: the role of hydroxybupropion.

https://www.ncbi.nlm.nih.gov/pubmed/23149928 [297]

“Bupropion is indicated to promote smoking cessation. Animal studies suggest that the pharmacologic activity of bupropion can be mediated by its major metabolite, hydroxybupropion. We measured plasma bupropion and its metabolite levels in a double-blind, placebo controlled, randomized smoking-cessation trial…These findings suggest that dosing of bupropion to achieve a hydroxybupropion level of 0.7 μg/ml or increasing bupropion dose for CYP2B6 slow metabolizers could improve bupropion's cessation outcomes.” [297]

Serum concentrations of hydroxybupropion for dose optimization of depressed patients treated with bupropion.

https://www.ncbi.nlm.nih.gov/pubmed/24452068 [298]

“Bupropion is a dopamine and norepinephrine reuptake inhibitor approved for the treatment of depression and smoking cessation. According to the recently published reviews, it is a candidate for

therapeutic drug monitoring (TDM) to improve therapeutic outcomes and reduce risks of intolerability or intoxication. In practice, however, the use of TDM is limited due to the chemical instability of bupropion. This investigation sought to determine if the major, active, and chemically stable metabolite 4- hydroxybupropion is a suitable measure to guide antidepressant drug therapy with bupropion…Despite multiple limitations of this naturalistic study, evidence could be given that the measurement of 4- hydroxybupropion in serum is suitable to perform TDM for bupropion. Blood levels should be above 860 ng/mL to attain therapeutic improvement. Potential sex differences in bupropion pharmacokinetics, probably due to differential activities of CYP2B6, should be taken into account when the drug is

prescribed.” [298]

A simple and sensitive LC-ESI-MS (ion trap) method for the determination of bupropion and its major metabolite, hydroxybupropion in rat plasma and brain microdialysates.

https://www.ncbi.nlm.nih.gov/pubmed/21315892 [299]

“A specific and highly sensitive liquid chromatography-electrospray mass spectrometry (LC-ESI-MS) method for the direct determination of bupropion (BUP) and its main metabolite hydroxybupropion

(HBUP) in rat plasma and brain microdialysate has been developed and validated. The analysis was performed on a Bonus RP C18 (100 mm × 2.1mm i.d., 3.5 μm particles) column using gradient elution

with the mobile phase consisting of acetonitrile and ammonium formate buffer (10mM, pH 4)…The method was validated in both plasma and microdialysate samples, and the obtained lower limit of

quantification (LLOQ) was 1.5 ng mL (-1) for BUP and HBUP in both matrices. The intra- and inter-day assay variability was less than 15% for both analytes. This LC-ESI-MS method provided simple

sampling, rapid clean-up and short analysis time (<9 min), applicable to the routine therapeutic monitoring and pharmacokinetic studies of BUP and HBUP.” [299]

Effect of CYP2B6*6 on Steady-State Serum Concentrations of Bupropion and Hydroxybupropion in Psychiatric Patients: A Study Based on Therapeutic Drug Monitoring Data.

https://www.ncbi.nlm.nih.gov/pubmed/25565674 [300]

“The clinical effect of bupropion is mediated by its active metabolite hydroxybupropion. Previous studies have reported conflicting impact of the CYP2B6*6 variant allele on the formation of hydroxybupropion from bupropion. The aim of this study was to clarify the effect of CYP2B6*6 and secondarily CYP2D6 genotype on steady-state serum concentrations of bupropion and hydroxybupropion in a large population of psychiatric patients…This study shows that the CYP2B6*6 variant allele is associated with significantly reduced formation of the active bupropion metabolite in psychiatric patients. Our findings suggest that dose-adjusted serum concentrations of hydroxybupropion at steady state is approximately halved in homozygous CYP2B6*6 carriers, which might imply risk of reduced clinical response in this patient subgroup. The CYP2D6 genotype does not affect hydroxybupropion concentrations and is therefore unlikely to impact bupropion treatment.” [300]

Human cytochrome P450 2B6 genetic variability in Botswana: a case of haplotype diversity and convergent phenotypes.

https://www.ncbi.nlm.nih.gov/pubmed/?term=29559695 [301]

“A total of 570 subjects were analyzed for CYP2B6 polymorphisms at position 516 G > T (rs3745274), 785 A > G (rs2279343) and 983 T > C (rs28399499). Samples were collected in three districts of

Botswana where the population belongs to Bantu (Serowe/Palapye and Chobe) and San-related (Ghanzi) ethnicity. The three districts showed different haplotype composition according to the ethnic

background but similar metabolic inferred phenotypes, with 59.12%, 34.56%, 2.10% and 4.21% of the subjects having, respectively, an extensive, intermediate, slow and rapid metabolic profile. The results

hint at the possibility of a convergent adaptation of detoxifying metabolic phenotypes despite a different haplotype structure due to the different genetic background. The main implication is that, while there is substantial homogeneity of metabolic inferred phenotypes among the country, the response to drugs metabolized via CYP2B6 could be individually associated to an increased risk of treatment failure and

toxicity. These are important facts since Botswana is facing malaria elimination and a very high HIV prevalence.”[301]

Determinants of the rate of nicotine metabolism and effects on smoking behavior

https://www.ncbi.nlm.nih.gov/pubmed/?term=17015050 [302]

“We investigated determinants of the rate of nicotine metabolism and effects on smoking behavior in a United Kingdom cohort who participated in a placebo-controlled trial of smoking cessation via nicotine

replacement therapy. Those who continued to smoke cigarettes at the 8-year follow-up formed our study group (N = 545). The ratio of the nicotine metabolite trans-3'-hydroxycotinine to cotinine in plasma

was used as an index of CYP2A6 activity and thus as a marker of the rate of nicotine metabolism. The nicotine metabolite ratio was associated with sex (P < .0001), CYP2A6 genotype (*1B, *2, *4, *9, and

*12) (P < .0001), CYP2B6 haplotype (*4-dominant) (P = .02), plasma nicotine concentration (P < .0001), and age (P = .02) but was not associated with dependence score (P > .20). The ratio also predicted the

number of cigarettes smoked at will per day, although the association was weak (F(1, 492) = 4.05, P = .04).”[302]

Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism.

https://www.ncbi.nlm.nih.gov/pubmed/?term=26389554 [303]

“Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n = 21), CYP2B6*1/*6 (n = 20), and CYP2B6*6/*6 (n = 17), and also CYP2B6*1/*4 (n = 1), CYP2B6*4/*6 (n = 3), and CYP2B6*5/*5 (n = 2) subjects, received single doses of IV and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry… R- and S-methadone apparent oral

clearance was threefold and fourfold greater in CYP2B6*4 carriers. IV and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with that of CYP2B6*1

homozygotes and greater in CYP2B6*4 carriers.”[303]

Multicenter study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in depression.

https://www.ncbi.nlm.nih.gov/pubmed/?term=22926595 [304]

“Inpatients and outpatients (n = 45; mean age, 51 years; range, 19-79 years) with major depressive episode received mirtazapine (MIR) for 8 weeks (30 mg/d on days 1-14 and 30-45 mg/d on days 15-

56)… Only in nonsmokers, plasma levels of S(+)-enantiomer of MIR and metabolites depended on the CYP2D6 genotype. Therefore, high CYP1A2 activity seen in smokers seems to mask the influence of

the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n = 8), S-OH-MIR concentrations were higher those in the other patients (n = 37).”[304]

CYP2B6 Genotype Guided Dosing of Propofol Anesthesia in the Elderly based on Nonparametric Population Pharmacokinetic Modeling and Simulations.

https://www.ncbi.nlm.nih.gov/pubmed/?term=28154789 [305]

“A total of 51 patients were included in the final PK analysis. A two-compartment gamma multiplicative error model adequately described the propofol concentration-time data. The precision of the goodnessof- fit plots resulted in an R2 of 0.927 and an R2 of 0.992 for the population prediction and individual predictions, respectively. Neither the UGT1A9 nor the CYP2B6 G516T gene variants resulted in

statistically significant PK parameter differences while the CYP2B6 A785G gene variants resulted in statistically significant differences for the elimination rate. Model-based dosing-simulations comparing

patients with the CYP2B6 AA & AG genotypes to both GG genotypes and patients from a multicenter trial suggest a 50% decrease in propofol infusion dose, to 25mg/kg/min, be made to result in

approximately equivalent drug exposures.”[305] 

Literature Summary: Cytochrome P450 2C9: (CYP2C9)

Pharmacogene Variation Consortium

https://www.pharmvar.org/ PharmGKB The Pharmacogenomics Knowledgebase.

https://www.pharmgkb.org/ [248]

Clinical applications of CYP genotyping in psychiatry.

http://www.ncbi.nlm.nih.gov/pubmed/25200585 [249]

Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects.

http://www.ncbi.nlm.nih.gov/pubmed/23089672 [250]

Applications of CYP450 testing in the clinical setting.

http://www.ncbi.nlm.nih.gov/pubmed/23588782 [251]

There is a large amount of variability in psychotropic drug response and variations in CYP450 genes, including CYP2C9, may impact this variability. There are several articles which review the relevant

clinical implications of altered CYP2C9 metabolism. [247-251]

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver.

http://www.ncbi.nlm.nih.gov/pubmed/20538623 [252]

“…we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme

activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes
enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity.” [252]

The dosing of atypical antipsychotics.

http://www.ncbi.nlm.nih.gov/pubmed/15883149 [261] 

“Dosage alterations of …quetiapine, dependent on cytochrome P450 3A (CYP3A), may be necessary when used with other drugs that inhibit or induce their metabolic enzymes. Genetic
variations of cytochrome P450 2D6 (CYP2D6) and drug-drug interactions causing inhibition (CYP2D6 and/or CYP3A) or induction (CYP3A) may be important for risperidone, and perhaps for

aripiprazole, dosing. Adding inhibitors may cause side effects more easily in drugs with a narrow therapeutic window, such as clozapine or risperidone, than in those with a wide therapeutic window, such as

olanzapine or aripiprazole.  Adding inducers may be associated with a gradual development of lost efficacy.” [261]

Cytochrome P450 2C9-CYP2C9.

http://www.ncbi.nlm.nih.gov/pubmed/20150829 [253]

“CYP2C9 is a phase I drug-metabolizing cytochrome P450 (CYP450) enzyme isoform that plays a major role in the oxidation of both xenobiotic and endogenous compounds… CYP2C9 is a phase I drug- metabolizing cytochrome P450 (CYP450) enzyme isoform that plays a major role in the oxidation of both xenobiotic and endogenous compounds.” [253]

Pharmacogenetics: from bench to byte— an update of guidelines.

http://www.ncbi.nlm.nih.gov/pubmed/21412232 [306]

“Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations… After systematic review of the literature, recommendations were developed

for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-Smethyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1),

uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).” [306]

Characterization of 107 genomic DNA reference materials for CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1: a GeT-RM and Association for Molecular Pathology collaborative project.

http://www.ncbi.nlm.nih.gov/pubmed/20889555 [254]

“…the Centers for Disease Control and Prevention’s Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetics testing community and the
Coriell Cell 52 Repositories, have characterized a panel of 107 genomic DNA reference materials for five loci (CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1) that are commonly included in pharmacogenetic testing panels and proficiency testing surveys. Genomic DNA from publicly available cell lines was sent to volunteer laboratories for genotyping. Each sample was tested in

three to six laboratories using a variety of commercially available or laboratory-developed platforms. The results were consistent among laboratories, with differences in allele assignments largely

related to the manufacturer’sassay design and variable nomenclature, especially for CYP2D6. The alleles included in the assay platforms varied, but most were identified in the set of 107 DNA samples.”

[254]

Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance.

http://www.ncbi.nlm.nih.gov/pubmed/21906384 [255]

“Regarding drug metabolism, specific polymorphisms to the cytochrome (CYP) P450 enzyme family are linked to phenotypes that describe reaction rates as "ultra", "intermediate", and "poor," as referenced to "extensive" metabolizers that are assigned to wildtype individuals. Activity scores is an alternate designation that provides more genotype-to-phenotype resolution. Understanding the relative
change in enzyme activities or rate of clearance of specific drugs relative to an individual's genotypes is an important component in the interpretation of pharmacogenomic data for personalized

medicine.” [255]

Polymorphisms of human cytochrome P450 2C9 and the functional relevance.

http://www.ncbi.nlm.nih.gov/pubmed/19715737 [256] 

“Human cytochrome P450 2C9 (CYP2C9) accounts for ∼20% of hepatic total CYP content and metabolizes ~15% clinical drugs such as phenytoin, S-warfarin, tolbutamide, losartan, and many nonsteroidal

anti-inflammatory agents (NSAIDs). CYP2C9 is highly polymorphic, with at least 33 variants of CYP2C9 (*1B through *34) being identified so far… The CYP2C9 polymorphisms are relevant for the efficacy and adverse effects of numerous NSAIDs, sulfonylurea antidiabetic drugs and, most critically, oral anticoagulants belonging to the class of vitamin K epoxide reductase inhibitors… Genetic testing of CYP2C9 is expected to play a role in predicting drug clearance and conducting individualized pharmacotherapy.” [256]

CYP2C9*3 Loss-of-Function Allele Is Associated With Acute Upper Gastrointestinal Bleeding Related to the Use of NSAIDs Other Than Aspirin.

http://www.ncbi.nlm.nih.gov/pubmed/20445534 [257]

“Nonsteroidal anti-inflammatory drugs (NSAIDs), other than aspirin, are to some extent metabolized by cytochrome P450 2C9 (CYP2C9). The CYP2C9 359Leu (CYP2C9*3) loss-of-function allele could be a

risk factor for acute upper gastrointestinal bleeding (AUGIB) related to the use of NSAIDs other than aspirin. To test this hypothesis, we performed a prospective, multicenter, case-case study in patients

hospitalized for AUGIB related to the use of NSAIDs… the results of the study support the hypothesis that the CYP2C9 359Leu allele is a robust risk factor for AUGIB related to the use of NSAIDs other than

aspirin.” [257]

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing.

http://www.ncbi.nlm.nih.gov/pubmed/21900891 [307]

“Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome

P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, in addition to known non-genetic factors, account for ~50% of warfarin dose variability.” [307] 

Genetically based impairment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized
medicine?

http://www.ncbi.nlm.nih.gov/pubmed/19422321 [308]

“Polymorphisms in CYP2C8 and CYP2C9 are common in all the human populations and many CYP2C8 and CYP2C9 gene variations cause decreased enzyme activity towards the NSAIDs aceclofenac,

celecoxib, diclofenac, ibuprofen, indomethazine, lornoxicam, meloxicam, naproxen, piroxicam, tenoxicam and valdecoxib… Individuals carrying the gene variants CYP2C8*3 (rs11572080; rs10509681),

CYP2C9*2 (rs1799853) or CYP2C9*3 (rs1057910) show increased risk of developing 53 acute gastrointestinal bleeding during the use of NSAID that are CYP2C8 or CYP2C9 substrates… We

present an overview of the current knowledge of relevant polymorphisms of CYP2C8 and CYP2C9 genes, their association with NSAID metabolism and pharmacokinetics and a meta-analysis that

confirms the clinical significance of these gene variations with regard to gastrointestinal bleeding.” [308]

Decreased warfarin clearance associated with the CYP2C9 R150H (*8) polymorphism.

http://www.ncbi.nlm.nih.gov/pubmed/22378156 [309]

“The cytochrome P450 (CYP) 2C9 R150H (*8) allele occurs commonly in African Americans and is associated with lower warfarin dose requirements… We observed a 30% reduction in the unbound oral

clearance of S-warfarin and a 25% lower R- to S-warfarin plasma concentration ratio in patients with the CYP2C9*8 allele (n = 12) as compared to CYP2C9*1 homozygotes (n = 26). Consistent with
these findings, the in vitro intrinsic clearance of S-warfarin was 30% lower with the cDNA-expressed R150H protein as compared to the wild-type protein. These data show that the R150H variant

protein expressed by the CYP2C9*8 allele is associated with lower S-warfarin clearance.” [309]

Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans.

http://www.ncbi.nlm.nih.gov/pubmed/15764711 [310]

“CYP2C9 is an important member of the cytochrome P450 enzyme superfamily with some 12  CYP2C9 alleles (*1-*12) being previously reported… Mean values of Km and Vmax for CYP2C9*1, *3, and *13

were 1.24, 1.61, and 2.79 microM and 0.83, 0.28, and 0.22 pmol/min/pmol, respectively. Intrinsic clearance values (Vmax/Km) for variant CYP2C9*3 and CYP2C9*13 on the basis of CYP2C9 protein levels

were separately decreased to 28% and 12% compared with wild type. In a subsequent clinical study, the AUC of lornoxicam was increased by 1.9-fold and its oral clearance (CL/F) decreased by 44%

in three CYP2C9*1/*13 subjects, compared with CYP2C9*1/*1 individuals. This suggests that the CYP2C9*13 allele is associated with decreased enzymatic activity both in vitro and in vivo.” [310]

Pharmacogenomic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options.

http://www.ncbi.nlm.nih.gov/pubmed/24523097 [311]

“Advancements in pharmacogenomics have introduced an increasing number of opportunities to bring personalized medicine into clinical practice. Understanding how and when to use this technology to guide pharmacotherapy used to treat psychiatric and neurological (neuropsychiatric) conditions remains a challenge for many clinicians. Currently, guidelines exist to assist clinicians in the use of existing genetic information for drug selection and/or dosing for the tricyclic antidepressants, carbamazepine, and phenytoin. Additional language in the product labeling suggests that genetic information may also be useful for determining the starting and target doses, as well as drug interaction potential, for a number of other drugs. In this review, we outline the current status of pharmacogenomic testing for neuropsychiatric drugs as it pertains to information contained in drug labeling, consensus guidelines, and test panels, as well as considerations related to obtaining tests for patients.” [311]

Role of cytochrome P450 genotype in the steps toward personalized drug therapy.

http://www.ncbi.nlm.nih.gov/pubmed/23226058 [312]

“Genetic polymorphism for cytochrome 450 (P450) enzymes leads to interindividual variability in the plasma concentrations of many drugs. In some cases, P450 genotype results in decreased enzyme

activity and an increased risk for adverse drug effects…The CYP2C9, CYP2C19, and CYP2D6 genes are the P450 genes most often cited. To date, integration of P450 genetic information into clinical

decision making is limited. However, some institutions are beginning to embrace routine P450 genotyping to assist in the treatment of their patients. Genotyping for P450 variants may carry less risk

for discrimination compared with genotyping for disease-associated variants. As such, P450 genotyping is likely to lead the way in the clinical implementation of pharmacogenomics. This review
discusses variability in the CYP2C9, CYP2C19, and CYP2D6 genes and the implications of this for drug efficacy and safety.” [312]

Cost-effectiveness of one-time genetic testing to minimize lifetime adverse drug reactions.

http://www.ncbi.nlm.nih.gov/pubmed/25987241 [288]

“We evaluated the cost-effectiveness of one-time pharmacogenomic testing for preventing adverse drug reactions (ADRs) over a patient's lifetime. We developed a Markov-based Monte Carlo microsimulation model to represent the ADR events in the lifetime of each patient. The base-case considered a 40-yearold patient. We measured health outcomes in life years (LYs) and quality-adjusted LYs (QALYs) and estimated costs using 2013 US$. In the base-case, one-time genetic testing had an incremental cost-effectiveness ratio (ICER) of $43,165 (95% confidence interval (CI) is ($42, 769, $43,561)) per additional LY and $53,680 per additional QALY (95% CI is ($53, 182, $54,179)), hence under the base-case onetime genetic testing is cost-effective. The ICER values were most sensitive to the average probability of death due to ADR, reduction in ADR rate due to genetic testing, mean ADR rate and cost of genetic testing.” [288]

Literature Summary: Cytochrome P450 2C19: (CYP2C19)

Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy.

http://www.ncbi.nlm.nih.gov/pubmed/24151799 [15]

Pharmacogene Variation Consortium

https://www.pharmvar.org/

PharmGKB The Pharmacogenomics Knowledgebase.

https://www.pharmgkb.org/ [248]

Clinical applications of CYP genotyping in psychiatry.

http://www.ncbi.nlm.nih.gov/pubmed/25200585 [249]

Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects.

http://www.ncbi.nlm.nih.gov/pubmed/23089672 [250]

Applications of CYP450 testing in the clinical setting.

http://www.ncbi.nlm.nih.gov/pubmed/23588782 [251]

There is a large amount of variability in psychotropic drug response and variations in CYP450 genes, including CYP2C19, may impact this variability. There are several articles which review the relevant

clinical implications of altered CYP2C19 metabolism and also review practice guidelines based upon patients’ altered 2C19 metabolic capacity. [15, 247-251] 

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver.

http://www.ncbi.nlm.nih.gov/pubmed/20538623 [252]

“…we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme

activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways

relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of

SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity.” [252]

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors.

http://www.ncbi.nlm.nih.gov/pubmed/25974703 [244]

“Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs,

thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine,

citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).” [244]

Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants.

http://www.ncbi.nlm.nih.gov/pubmed/23486447 [313]

“Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine,

doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active 55 metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo

hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants.” [313]

Pharmacogenetics: from bench to byte— an update of guidelines.

http://www.ncbi.nlm.nih.gov/pubmed/21412232 [306]

“Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations… After systematic review of the literature, recommendations were

developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-Smethyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase

(VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).” [306]

Characterization of 107 Genomic DNA Reference Materials for CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1.

http://www.ncbi.nlm.nih.gov/pubmed/20889555 [254]

“…the Centers for Disease Control and Prevention’s Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetics testing community and the Coriell Cell

Repositories, have characterized a panel of 107 genomic DNA reference materials for five loci (CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1) that are commonly included in pharmacogenetic testing panels and proficiency testing surveys. Genomic DNA from publicly available cell lines was sent to volunteer laboratories for genotyping. Each sample was tested in three to six laboratories using a variety of commercially available or laboratory-developed platforms. The results were consistent among laboratories, with differences in allele assignments largely related to the manufacturer’s assay design and variable nomenclature, especially for CYP2D6. The alleles included in the assay platforms varied, but most were identified in the set of 107 DNA samples.” [254]

Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance.

http://www.ncbi.nlm.nih.gov/pubmed/21906384 [255]

“Regarding drug metabolism, specific polymorphisms to the cytochrome (CYP) P450 enzyme family are linked to phenotypes that describe reaction rates as "ultra", "intermediate", and "poor," as referenced to "extensive" metabolizers that are assigned to wildtype individuals. Activity scores is an alternate designation that provides more genotype-to-phenotype resolution. Understanding the relative change in

enzyme activities or rate of clearance of specific drugs relative to an individual's genotypes is an important component in the interpretation of pharmacogenomic data for personalized medicine.” [255]

Metabolic ratios of psychotropics as indication of cytochrome P450 2D6/2C19 genotype.

http://www.ncbi.nlm.nih.gov/pubmed/16044105 [314]

“The relationships between the observed metabolic ratios and CYP2D6 and/or CYP2C19 genotype were characterized using nonparametric statistical analysis… According to these data, correlations exist

between the log (MR) of venlafaxine, amitriptyline, and risperidone and the genotype of the CYP enzymes involved in their metabolism. From the ranges of log (MR) defined here, a high percentage of

aberrant metabolizers can be detected even when patients are not routinely genotyped. Thus, the metabolic ratio may serve as an indication of when genotyping should be considered.” [314]

CYP2C19 variation and citalopram response.

http://www.ncbi.nlm.nih.gov/pubmed/21192344 [315]

“CYP2C19 and CYP3A4 play a primary role in citalopram metabolism, whereas CYP2D6 plays a  secondary role… Generally, patients who had CYP2C19 genotypes associated with decreased metabolism were less likely to tolerate citalopram than those with increased metabolism, although this difference was not statistically significant (P = 0.06). However, patients with the inactive 2C19*2 allele

had significantly lower odds of tolerance (P = 0.02)… this study showed that variations in CYP2C19 were associated with tolerance and remission in a large sample of White non-Hispanic patients treated

with citalopram.” [315]

Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients.

http://www.ncbi.nlm.nih.gov/pubmed/17625515 [316]

56 

The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients.

http://www.ncbi.nlm.nih.gov/pubmed/19884907 [317]

CYP2C19*17 affects R-warfarin plasma clearance and warfarin INR/dose ratio in patients on stable warfarin maintenance therapy.

http://www.ncbi.nlm.nih.gov/pubmed/25652102 [318]

Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement.

http://www.ncbi.nlm.nih.gov/pubmed/20083681 [242]

A recently explored CYP2C19*17 allelic variant has been linked to increased transcriptional activity, resulting in increased metabolism of CYP2C19 substrates. The *17 allele leads to ultra rapid metabolism of CYP2C19 substrates, producing lower plasma levels of drugs and probable decreases in efficacy. [242, 316-318]

Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereo selective metabolism in forensic autopsy cases.

http://www.ncbi.nlm.nih.gov/pubmed/25245581 [319]

“We investigated whether polymorphisms in the CYP2D6 and CYP2C19 genes influence the metabolic ratios and enantiomeric S/R ratios of venlafaxine (VEN) and its metabolites O-desmethylvenlafaxine

(ODV), N-desmethylvenlafaxine (NDV) and N, O-didesmethylvenlafaxine (DDV) in blood from forensic autopsy cases…Our results show that the CYP2D6 genotype influences the O-demethylation whereas

CYP2C19 influences the N-demethylation of VEN and its metabolites. In addition, we show a stereoselective metabolism where CYP2D6 favors the R-enantiomer whereas CYP2C19 favors the Senantiomer.”

[319]

Functional characterization of 21 CYP2C19 allelic variants for clopidogrel 2-oxidation.

http://www.ncbi.nlm.nih.gov/pubmed/25001882 [320]

“Genetic variations in cytochrome P450 2C19 (CYP2C19) contribute to interindividual variability in the metabolism of therapeutic agents such as clopidogrel… This study evaluated the in vitro oxidation of

clopidogrel by 21 CYP2C19 variants harboring amino acid substitutions… Among the 21 CYP2C19 variants, 12 (that is, CYP2C19.5A, CYP2C19.5B, CYP2C19.6, CYP2C19.8, CYP2C19.9, CYP2C19.10,

CYP2C19.14, CYP2C19.16, CYP2C19.19, CYP2C19.22, CYP2C19.24 and CYP2C19.25) showed no or markedly low activity compared with the wild-type protein CYP2C19.1B. This comprehensive in vitro

assessment provided insights into the specific metabolic activities of CYP2C19 proteins encoded by variant alleles, and this may to be valuable when interpreting the results of in vivo studies.” [320]

Evaluation of the effects of 20 nonsynonymous single nucleotide polymorphisms of CYP2C19 on Smephenytoin 4'-hydroxylation and omeprazole 5'-hydroxylation.

http://www.ncbi.nlm.nih.gov/pubmed/21325430 [321]

“CYP2C19 is a highly polymorphic enzyme that affects the metabolism of a wide range of therapeutic drugs…The objective of this study was to functionally characterize 20 nsSNPs of CYP2C19, distributed

throughout the entire coding region, most of which have not been thoroughly characterized…CYP2C19.5B, CYP2C19.6, and CYP2C19.8 were found to be catalytically inactive…CYP2C19.9, CYP2C19.10, CYP2C19.16, CYP2C19.18, CYP2C19.19, A161P, W212C, and D360N were substantially altered in catalytic properties in comparison with the WT, with each of these variants exhibiting either dramatically decreased catalytic activities or higher K(m) values.” [321]

Genomics and pharmacogenomics of schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/20718829 [273]

“Schizophrenia (SCZ) is among the most disabling of mental disorders…SCZ has a heritability estimated at 60-90%. Genetic studies in SCZ have revealed the presence of chromosome anomalies, copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single nucleotide polymorphisms (SNPs) in microRNA genes, mitochondrial

DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the

57

positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and

95% of CYP3A4. About 10-20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the tri-genic cluster integrated by

the CYP2D6+CYP2C19+CYP2C9 genes. The pharmacogenomic response of SCZ patients to conventional psychotropic drugs also depends on genetic variants associated with SCZ-related genes.

Consequently, the incorporation of pharmacogenomic procedures both to drugs in development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system

(CNS) disorders.” [273]

Pharmacogenomic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options.

http://www.ncbi.nlm.nih.gov/pubmed/24523097 [311]

“Advancements in pharmacogenomics have introduced an increasing number of opportunities to bring personalized medicine into clinical practice. Understanding how and when to use this technology to guide pharmacotherapy used to treat psychiatric and neurological (neuropsychiatric) conditions remains a challenge for many clinicians. Currently, guidelines exist to assist clinicians in the use of existing genetic information for drug selection and/or dosing for the tricyclic antidepressants, carbamazepine, and phenytoin. Additional language in the product labeling suggests that genetic information may also be useful for determining the starting and target doses, as well as drug interaction potential, for a number of other drugs. In this review, we outline the current status of pharmacogenomic testing for neuropsychiatric drugs as it pertains to information contained in drug labeling, consensus guidelines, and test panels, as well as considerations related to obtaining tests for patients.” [311]

Role of cytochrome P450 genotype in the steps toward personalized drug therapy.

http://www.ncbi.nlm.nih.gov/pubmed/23226058 [312]

“Genetic polymorphism for cytochrome 450 (P450) enzymes leads to interindividual variability in the plasma concentrations of many drugs. In some cases, P450 genotype results in decreased enzyme

activity and an increased risk for adverse drug effects. For example, individuals with the CYP2D6 loss-of function genotype are at increased risk for ventricular arrhythmia if treated with usual doses of

thioridazine. In other cases, P450 genotype may influence the dose of a drug required to achieve a desired effect. This is the case with warfarin, with lower doses often necessary in carriers of a variant

CYP2C9*2 or *3 allele to avoid supra-therapeutic anticoagulation. When a prodrug, such as clopidogrel or codeine, must undergo hepatic biotransformation to its active form, a loss-of-function P450 genotype leads to reduced concentrations of the active drug and decreased drug efficacy. In contrast, patients with multiple CYP2D6 gene copies are at risk for opioid-related toxicity if treated with usual doses of codeinecontaining analgesics. At least 25 drugs contain information in their US Food and Drug Administrationapproved labeling regarding P450 genotype. The CYP2C9, CYP2C19, and CYP2D6 genes are the P450 genes most often cited. To date, integration of P450 genetic information into clinical decision making is limited. However, some institutions are beginning to embrace routine P450 genotyping to assist in the treatment of their patients. Genotyping for P450 variants may carry less risk for discrimination compared with genotyping for disease-associated variants. As such, P450 genotyping is likely to lead the way in the clinical implementation of pharmacogenomics. This review discusses variability in the CYP2C9, CYP2C19, and CYP2D6 genes and the implications of this for drug efficacy and safety.” [312]

Pharmacogenomics study in a Taiwan methadone maintenance cohort.

http://www.ncbi.nlm.nih.gov/pubmed/25278738 [284]

“Pharmacogenomics is research to study the drug treatment responses in subgroups of patients according to their genetic variants or genetic expression information. Methadone maintenance treatment, which is usually prescribed for patients with heroin dependence, was launched in Taiwan by the government in 2006. In this study, 366 patients who had taken methadone continually in the previous 7 days were examined. Data from administration of the Treatment Outcomes Profile (TOP), Severity of Dependence Scale (SDS), Clinical Opioid Withdrawal Scale (COWS), and Treatment Emergent Symptoms Scale (TESS) were obtained from patients' report records. Genes encoding the liver cytochrome P-450 (CYP) enzymes that are involved with the metabolism of methadone (CYP2B6, 3A4 and 2C19) were selected and genotyped in this cohort. We found that the SNPs on CYP2B6 were associated with plasma S-methadone concentration; SNPs on CYP3A4 were associated with withdrawal symptoms and side effects; and SNPs on CYP2C19 were associated with methadone dose. SNPs in the genes encoding the morphine phase II metabolic enzyme, UGT2B7, were associated with 

58

withdrawal symptom scores. In pharmacodynamic genes, the SNPs on OPRM1 were associated with insomnia and change in libido side effects. We conclude that SNP markers may be useful for future

methadone dosage adjustment and to reduce adverse reactions.” [284]

Cost-effectiveness of one-time genetic testing to minimize lifetime adverse drug reactions.

http://www.ncbi.nlm.nih.gov/pubmed/25987241 [288]

“We evaluated the cost-effectiveness of one-time pharmacogenomic testing for preventing adverse drugreactions (ADRs) over a patient's lifetime. We developed a Markov-based Monte Carlo microsimulation

model to represent the ADR events in the lifetime of each patient. The base-case considered a 40-yearoldpatient. We measured health outcomes in life years (LYs) and quality-adjusted LYs (QALYs) and

estimated costs using 2013 US$. In the base-case, one-time genetic testing had an incremental costeffectiveness ratio (ICER) of $43,165 (95% confidence interval (CI) is ($42, 769, $43,561)) per additional

LY and $53,680 per additional QALY (95% CI is ($53, 182, $54,179)), hence under the base-case onetime genetic testing is cost-effective. The ICER values were most sensitive to the average probability of

death due to ADR, reduction in ADR rate due to genetic testing, mean ADR rate and cost of genetic testing.” [288]

Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for Psychiatric Precision Medicine.

http://www.ncbi.nlm.nih.gov/pubmed/27289413 [322]

“Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (e.g, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19.” [322]

The CYP2C19 Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers with CYP2C19*35 and CYP2C19*2 Alleles.

https://www.ncbi.nlm.nih.gov/pubmed/26021325 [323]

“CYP2C19 rs12769205 alters an intron 2 branch point adenine leading to an alternative mRNA in human liver with complete inclusion of intron 2 (exon 2B). rs12769205 changes the mRNA reading

frame, introduces 87 amino acids, and leads to a premature stop codon. The 1000 Genomes project indicated rs12769205 is in linkage disequilibrium with rs4244285 on CYP2C19*2, but found alone on

CYP2C19*35 in Blacks. Minigenes containing rs12769205 transfected into HepG2 cells demonstrated this single nucleotide polymorphism (SNP) alone leads to exon 2B and decreases CYP2C19 canonical

mRNA. A residual amount of CYP2C19 protein was detectable by quantitative proteomics with tandem mass spectrometry in CYP2C19*2/*2 and *1/*35 liver microsomes with an exon 2 probe. However, an

exon 4 probe, downstream from rs12769205, but upstream of rs4244285, failed to detect CYP2C19 protein in livers homozygous for rs12769205, demonstrating rs12769205 alone can lead to complete

loss of CYP2C19 protein. CYP2C19 genotypes and mephenytoin phenotype were compared in 104 Ethiopians. Poor metabolism of mephenytoin was seen in persons homozygous for both rs12769205

and rs4244285 (CYP2C19*2/*2), but with little effect on mephenytoin disposition of CYP2C19*1/*2, CYP2C19*1/*3, or CYP2C19*1/*35 heterozygous alleles.” [323]

Literature Summary: Cytochrome P450 2D6: (CYP2D6)

Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric

pharmacotherapy.

http://www.ncbi.nlm.nih.gov/pubmed/24151799 [15]

59

Pharmacogenetics of second-generation antipsychotics.

http://www.ncbi.nlm.nih.gov/pubmed/24897292 [20]

Pharmacogene Variation Consortium

https://www.pharmvar.org/

PharmGKB The Pharmacogenomics Knowledgebase.

https://www.pharmgkb.org/ [248]

Clinical applications of CYP genotyping in psychiatry.

http://www.ncbi.nlm.nih.gov/pubmed/25200585 [249]

Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and

endogenous effects.

http://www.ncbi.nlm.nih.gov/pubmed/23089672 [250]

Applications of CYP450 testing in the clinical setting.

http://www.ncbi.nlm.nih.gov/pubmed/23588782 [251]

Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I.

http://www.ncbi.nlm.nih.gov/pubmed/19817501 [324]

Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part II.

http://www.ncbi.nlm.nih.gov/pubmed/19902987 [325]

Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of

CYP2D6.

http://www.ncbi.nlm.nih.gov/pubmed/24088607 [326]

Pharmacokinetics of venlafaxine extended release 75 mg and desvenlafaxine 50 mg in healthy CYP2D6

extensive and poor metabolizers: a randomized, open-label, two-period, parallel-group, crossover study.

http://www.ncbi.nlm.nih.gov/pubmed/21288052 [327]

The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions

and discontinuation.

http://www.ncbi.nlm.nih.gov/pubmed/15669884 [328]

There are numerous studies which support the fact that CYP2D6 metabolizer status can lead to altered drug clearance and levels of active metabolites of psychiatric medications. These changes may lead to

increased risk for side effects or treatment inefficacy. For example, CYP2D6 poor metabolizer genotype is associated with increased risk for side effects and medication discontinuation. [15, 20, 247-251, 324-

328]

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver.

http://www.ncbi.nlm.nih.gov/pubmed/20538623 [252]

“…we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme

activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways

relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of

SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity.” [252]

CYP450 pharmacogenetic treatment strategies for antipsychotics: a review of the evidence.

http://www.ncbi.nlm.nih.gov/pubmed/23870808 [258]

“CYP2D6, CYP1A2, and CYP3A4/5 are major enzymes in the metabolism of antipsychotics and polymorphisms of alleles for these proteins are associated with altered plasma levels… Numerous

studies have shown a significant association between genotype and adverse effects, such as CYP2D6 polymorphisms and tardive dyskinesia. This review summarizes evidence for the role of CYP450

genetic variants in the response to antipsychotic medications and the clinical implications of pharmacogenetics in the management of patients with schizophrenia.” [258]

The Dosing of Atypical Antipsychotics.

http://www.ncbi.nlm.nih.gov/pubmed/15883149 [261]

“Drug-drug interactions or genetic variability may require using doses different from those recommended for atypical antipsychotics… Genetic variations of cytochrome P450 2D6 (CYP2D6) and drug-drug

interactions causing inhibition (CYP2D6 and/or CYP3A) or induction (CYP3A) may be important for risperidone, and perhaps for aripiprazole, dosing. Adding inhibitors may cause side effects more easily

in drugs with a narrow therapeutic window, such as clozapine or risperidone, than in those with a wide therapeutic window, such as olanzapine or aripiprazole. Adding inducers may be associated with a

gradual development of lost efficacy.” [261]

Pharmacogenetics: from bench to byte— an update of guidelines.

http://www.ncbi.nlm.nih.gov/pubmed/21412232 [306]

“…the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics-based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).” [306]

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype.

http://www.ncbi.nlm.nih.gov/pubmed/22205192 [245]

“Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultra rapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.” [245]

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors.

http://www.ncbi.nlm.nih.gov/pubmed/25974703 [244]

“Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs,

thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).” [244]

Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants.

http://www.ncbi.nlm.nih.gov/pubmed/23486447 [313]

“Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine,

doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo

hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants.” [313]

Characterization of 107 Genomic DNA Reference Materials for CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1: a GeT-RM and Association for Molecular Pathology collaborative project.

http://www.ncbi.nlm.nih.gov/pubmed/20889555 [254]

“…the Centers for Disease Control and Prevention’s Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetics testing community and the Coriell Cell

Repositories, have characterized a panel of 107 genomic DNA reference materials for five loci (CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1) that are commonly included in 61 pharmacogenetic testing panels and proficiency testing surveys. Genomic DNA from publicly available cell lines was sent to volunteer laboratories for genotyping. Each sample was tested in three to six laboratories using a variety of commercially available or laboratory-developed platforms. The results were consistent among laboratories, with differences in allele assignments largely related to the manufacturer’s assay design and variable nomenclature, especially for CYP2D6. The alleles included in the assay platforms varied, but most were identified in the set of 107 DNA samples.” [254]

Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance.

http://www.ncbi.nlm.nih.gov/pubmed/21906384 [255]

“Regarding drug metabolism, specific polymorphisms to the cytochrome (CYP) P450 enzyme family are linked to phenotypes that describe reaction rates as "ultra", "intermediate", and "poor," as referenced to "extensive" metabolizers that are assigned to wildtype individuals. Activity scores is an alternate designation that provides more genotype-to-phenotype resolution. Understanding the relative change in

enzyme activities or rate of clearance of specific drugs relative to an individual's genotypes is an important component in the interpretation of pharmacogenomic data for personalized medicine.” [255]

Metabolic ratios of psychotropics as indication of cytochrome P450 2D6/2C19 genotype.

http://www.ncbi.nlm.nih.gov/pubmed/16044105 [314]

“The relationships between the observed metabolic ratios and CYP2D6 and/or CYP2C19 genotype were characterized using nonparametric statistical analysis. A clear correlation was observed between

the CYP2D6 genotype and the metabolic ratio of venlafaxine.” [314] 

CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure.

http://www.ncbi.nlm.nih.gov/pubmed/17301689 [329]

“Our study shows that (i) CYP2D6 diversity is far greater within than between populations and groups thereof, (ii) null or low-activity variants occur at high frequencies in various areas of the world, (iii)

linkage disequilibrium is lowest in Africa and highest in the Americas. Patterns of variation, within and among populations, are similar to those observed for other autosomal markers (e.g. microsatellites and

protein polymorphisms), suggesting that the diversity observed at the CYP2D6 locus reflects the same factors affecting variation at random genome markers.” [329]

CYP2D6 genotype information to guide pimozide treatment in adult and pediatric patients: basis for the U.S. Food and Drug Administration's new dosing recommendations.

http://www.ncbi.nlm.nih.gov/pubmed/23059146 [330]

“The occurrence of pimozide-induced arrhythmias is concentration dependent. Hence, it is important for prescribers to consider causes of increased pimozide exposure. This article summarizes the U.S. Food and Drug Administration's (FDA's) review of drug interaction and pharmacogenomic studies and discusses pharmacokinetic simulations we performed to develop new cytochrome P450 2D6 (CYP2D6)

genotype-guided dosing recommendations for pimozide.” [330] 

Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: a secondary analysis of 4 studies in major depressive disorder.

http://www.ncbi.nlm.nih.gov/pubmed/20441720 [331]

“Compared with PMs, EMs had significantly greater mean changes from baseline on 4 of 5 depression rating scales (all 4 comparisons, P ≤ .020). A significantly greater percentage of EMs achieved response

or remission by most measures compared with PMs (4 of 5 comparisons, P ≤ .015). Rates of discontinuation and AEs did not differ significantly between EMs and PMs.” [331]

Clinical pharmacokinetics of atomoxetine.

http://www.ncbi.nlm.nih.gov/pubmed/15910008 [332]

Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites.

http://www.ncbi.nlm.nih.gov/pubmed/26254792 [333]

CYP2D6 predicted metabolizer status and safety in adult patients with attention-deficit hyperactivity

disorder participating in a large placebo-controlled atomoxetine maintenance of response clinical trial.

http://www.ncbi.nlm.nih.gov/pubmed/25919121 [334]

Several studies have shown that CYP2D6 polymorphism can lead to altered atomoxetine metabolism and varied blood levels, as well as increased risk of side effects. The mean exposure to active moieties

of atomoxetine was markedly higher in subjects with the CYP2D6*10/*10 genotype compared to that in those with the CYP2D6* WT/*WT genotype. Poor metabolizers had higher frequencies of dry mouth,

erectile dysfunction, hyperhidrosis, insomnia, and urinary retention compared with the other metabolizer groups. [332-334]

Cytochrome P450 2D6 genotype affects the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects: comparison of traditional phenotype and activity score systems.

http://www.ncbi.nlm.nih.gov/pubmed/25967538 [335]

“…the pharmacokinetics of controlled-release paroxetine after a single administration was affected by CYP2D6 polymorphisms. Both the traditional phenotype and the activity score systems performed well

and distinguished subjects with different drug exposures. The activity score system provided a more detailed classification for the subjects.” [335]

Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort.

http://www.ncbi.nlm.nih.gov/pubmed/26129906 [336]

“High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, may lead to suboptimal drug concentration… Genetic polymorphisms of CYP2D6

play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a

personalized dosage adjustment during risperidone treatment.” [336]

Impact of multiple inhibitors or substrates of cytochrome P450 2D6 on plasma risperidone levels in patients on polypharmacy.

http://www.ncbi.nlm.nih.gov/pubmed/18728628 [337]

“CYP2D6 catalyzes the conversion of risperidone to the active metabolite 9-OH-risperidone…Concentration-to-dose (C: D) ratios of risperidone and 9-OH-risperidone in 218 patients were associated with the number of concomitantly used substrates or inhibitors of CYP2D6. The C: D ratios of risperidone in patients with 0, 1, and >1 numbers of CYP2D6 inhibitors were 2.6, 8.5, and 17 nmol L-1

mg-1, respectively. Differences between the groups were highly significant (p < 0.001). All patients with >1 CYP2D6 inhibitors were administered at least 1 potent CYP2D6 inhibitor, that is fluoxetine,

paroxetine, thioridazine, and/or levomepromazine. The C:D ratios of the active moiety (risperidone + 9- OH-risperidone) in patients with 0, 1, and >1 numbers of concomitant CYP2D6 inhibitors were 17, 24,

and 30 nmol L-1 mg-1, respectively (p = 0.001), which was explained by higher levels of risperidone without any change in the levels of 9-OH-risperidone… An indication for risperidone drug monitoring

should therefore include concomitant medication with established CYP inhibitors.” [337]

CYP2D6 genetic polymorphisms and their relevance for poisoning due to amphetamines, opioid

analgesics and antidepressants.

http://www.ncbi.nlm.nih.gov/pubmed/25998998 [338]

“This review will focus specifically on CYP2D6 genetic polymorphisms and their relevance for poisoning due to amphetamines, opioid analgesics and antidepressants in humans…Either poor or

extensive/ultra-rapid CYP2D6 metabolizers may be exposed to toxic effects of amphetamines, opioid analgesics and antidepressants. In these three categories, the level of evidence is substance

dependent, with differences within the same pharmacological class.” [338]

Opioid metabolism.

http://www.ncbi.nlm.nih.gov/pubmed/19567715 [339]

“Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective

analgesia with acceptable tolerability… This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may

compromise effective pain management.” [339]

CYP2D6 phenotype-specific codeine population pharmacokinetics.

http://www.ncbi.nlm.nih.gov/pubmed/25562725 [340]

“We aimed to develop a codeine pharmacokinetic pathway model for codeine and its metabolites that incorporates the effects of genetic polymorphisms… The population model indicated that about 10% of

a codeine dose was converted to morphine in poor-metabolizer phenotype subjects. The model also showed that about 40% of a codeine dose was converted to morphine in EM subjects, and about 51%

was converted to morphine in ultra rapid-metabolizers… Our study suggests that pharmacogenetics for personalized dosing might be most effectively advanced by studying the interplay between

pharmacogenetics, population pharmacokinetics, and clinical pharmacokinetics.” [340]

Individualized Hydrocodone Therapy Based on Phenotype, Pharmacogenetics, and Pharmacokinetic Dosing.

http://www.ncbi.nlm.nih.gov/pubmed/25621429 [341]

“Our results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize [hydrocodone] HC dosing, while adding enhanced opportunity to account for its conversion to HM in the

body.” [341]

Genomics and pharmacogenomics of schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/20718829 [273]

“Schizophrenia (SCZ) is among the most disabling of mental disorders…SCZ has a heritability estimated at 60-90%. Genetic studies in SCZ have revealed the presence of chromosome anomalies,

copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single nucleotide polymorphisms (SNPs) in microRNA genes, mitochondrial

DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the

positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major

substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and

95% of CYP3A4. About 10-20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the tri-genic cluster integrated by

the CYP2D6+CYP2C19+CYP2C9 genes. The pharmacogenomic response of SCZ patients to conventional psychotropic drugs also depends on genetic variants associated with SCZ-related genes.

Consequently, the incorporation of pharmacogenomic procedures both to drugs in development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system

(CNS) disorders.” [273]

Pharmacogenomics can improve antipsychotic treatment in schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/23606027 [274]

“Schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population, and heritability of up to 80%. Drug therapy is an important approach to treating the disease. However, the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects. Many studies have indicated that nearly 30% of patients exhibit little or no improvements associated with

antipsychotics. The response of individual patients who are given the same dose of the same drug varies considerably. In addition, antipsychotic drugs are often accompanied by adverse drug reactions (ADRs), which can cause considerable financial loss in addition to the obvious societal harm. So, it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity. There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians. Individual differences in drug response is due to a combination of many complex factors including ADEM (absorption, distribution, metabolism, excretion) process, transporting, binding with receptor and intracellular signal transduction. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response. In addition, epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients. In this review, we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolicenzymes (CYP2D6, CYP1A2, CYP3A4, etc.), drug transporters (mainly ABCB1) and neurotransmitter receptors (dopamine receptors and serotonin receptors, etc.). We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications.” [274]

Pharmacogenomic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options.

http://www.ncbi.nlm.nih.gov/pubmed/24523097 [311]

“Advancements in pharmacogenomics have introduced an increasing number of opportunities to bring personalized medicine into clinical practice. Understanding how and when to use this technology to guide pharmacotherapy used to treat psychiatric and neurological (neuropsychiatric) conditions remains a challenge for many clinicians. Currently, guidelines exist to assist clinicians in the use of existing genetic information for drug selection and/or dosing for the tricyclic antidepressants, carbamazepine, and phenytoin. Additional language in the product labeling suggests that genetic information may also be useful for determining the starting and target doses, as well as drug interaction potential, for a number of other drugs. In this review, we outline the current status of pharmacogenomic testing for neuropsychiatric drugs as it pertains to information contained in drug labeling, consensus guidelines, and test panels, as well as considerations related to obtaining tests for patients.” [311]

Role of cytochrome P450 genotype in the steps toward personalized drug therapy.

http://www.ncbi.nlm.nih.gov/pubmed/23226058 [312]

“Genetic polymorphism for cytochrome 450 (P450) enzymes leads to interindividual variability in the plasma concentrations of many drugs. In some cases, P450 genotype results in decreased enzyme

activity and an increased risk for adverse drug effects. For example, individuals with the CYP2D6 loss-offunction genotype are at increased risk for ventricular arrhythmia if treated with usual doses of

thioridazine. In other cases, P450 genotype may influence the dose of a drug required to achieve a desired effect. This is the case with warfarin, with lower doses often necessary in carriers of a variant

CYP2C9*2 or *3 allele to avoid supra-therapeutic anticoagulation. When a prodrug, such as clopidogrel or codeine, must undergo hepatic biotransformation to its active form, a loss-of-function P450 genotype leads to reduced concentrations of the active drug and decreased drug efficacy. In contrast, patients with multiple CYP2D6 gene copies are at risk for opioid-related toxicity if treated with usual doses of codeinecontaining analgesics. At least 25 drugs contain information in their US Food and Drug Administrationapproved labeling regarding P450 genotype. The CYP2C9, CYP2C19, and CYP2D6 genes are the P450 genes most often cited. To date, integration of P450 genetic information into clinical decision making is limited. However, some institutions are beginning to embrace routine P450 genotyping to assist in the treatment of their patients. Genotyping for P450 variants may carry less risk for discrimination compared with genotyping for disease-associated variants. As such, P450 genotyping is likely to lead the way in the clinical implementation of pharmacogenomics. This review discusses variability in the CYP2C9, CYP2C19, and CYP2D6 genes and the implications of this for drug efficacy and safety.” [312]

Copy number variations' effect on drug response still overlooked.

http://www.ncbi.nlm.nih.gov/pubmed/25742449 [342]

Cost-effectiveness of one-time genetic testing to minimize lifetime adverse drug reactions.

http://www.ncbi.nlm.nih.gov/pubmed/25987241 [288]

“We evaluated the cost-effectiveness of one-time pharmacogenomic testing for preventing adverse drug reactions (ADRs) over a patient's lifetime. We developed a Markov-based Monte Carlo microsimulation model to represent the ADR events in the lifetime of each patient. The base-case considered a 40-yearold patient. We measured health outcomes in life years (LYs) and quality-adjusted LYs (QALYs) and estimated costs using 2013 US$. In the base-case, one-time genetic testing had an incremental costeffectiveness ratio (ICER) of $43,165 (95% confidence interval (CI) is ($42, 769, $43,561)) per additional LY and $53,680 per additional QALY (95% CI is ($53, 182, $54,179)), hence under the base-case onetime genetic testing is cost-effective. The ICER values were most sensitive to the average probability of death due to ADR, reduction in ADR rate due to genetic testing, mean ADR rate and cost of genetic testing.” [288]

Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for

Psychiatric Precision Medicine.

http://www.ncbi.nlm.nih.gov/pubmed/27289413 [322]

“Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (e.g, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19.” [322]

Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of

aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol.

http://www.ncbi.nlm.nih.gov/pubmed/26514968 [343]

“Overall, 6.1 % UM (n = 5), 25.6 % EM-f (n = 21), 46.3 % EM-s (n = 38), 1.2 % EM-s/EM-f (n = 1), 6.1 % IM (n = 5), and 14.6 % PM (n = 12) were found, taking co-administration of strong and moderate CYP2D6 inhibitors into account (pheno-conversion). It was demonstrated that CYP2D6 polymorphisms affect the serum concentrations of aripiprazole (n = 18), haloperidol (n = 11), risperidone (n = 20), and

zuclopenthixol (n = 6), while no influence was seen on the paliperidone serum concentrations (n = 31).” [343]

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease.

http://www.ncbi.nlm.nih.gov/pubmed/27335380 [344]

“Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health

record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June

2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultrarapid

metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer

genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our

efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized

pediatric populations.” [344]

Literature Summary: Cytochrome P450 3A4/5: (CYP3A4/5)

Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric

pharmacotherapy.

http://www.ncbi.nlm.nih.gov/pubmed/24151799 [15]

Pharmacogenetics of second-generation antipsychotics.

http://www.ncbi.nlm.nih.gov/pubmed/24897292 [20]

Pharmacogene Variation Consortium

https://www.pharmvar.org/

PharmGKB The Pharmacogenomics Knowledgebase.

https://www.pharmgkb.org/ [248]

Clinical applications of CYP genotyping in psychiatry.

http://www.ncbi.nlm.nih.gov/pubmed/25200585 [249]

Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and

endogenous effects.

http://www.ncbi.nlm.nih.gov/pubmed/23089672 [250]

Applications of CYP450 testing in the clinical setting.

http://www.ncbi.nlm.nih.gov/pubmed/23588782 [251]

There is a large amount of variability in psychotropic drug response and variations in CYP450 genes, including CYP3A4/5, may impact this variability. There are several articles which review the relevant

clinical implications of altered CYP3A4/5 metabolism. [15, 20, 247-251] 

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver.

http://www.ncbi.nlm.nih.gov/pubmed/20538623 [252]

“…we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme

activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways

relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of

SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity.” [252]

CYP450 pharmacogenetic treatment strategies for antipsychotics: a review of the evidence.

http://www.ncbi.nlm.nih.gov/pubmed/23870808 [258]

“CYP2D6, CYP1A2, and CYP3A4/5 are major enzymes in the metabolism of antipsychotics and polymorphisms of alleles for these proteins are associated with altered plasma levels… Numerous studies have shown a significant association between genotype and adverse effects, such as CYP2D6 polymorphisms and tardive dyskinesia. This review summarizes evidence for the role of CYP450 genetic variants in the response to antipsychotic medications and the clinical implications of pharmacogenetics in the management of patients with schizophrenia.” [258]

The dosing of atypical antipsychotics.

http://www.ncbi.nlm.nih.gov/pubmed/15883149 [261]

“Dosage alterations of …quetiapine, dependent on cytochrome P450 3A (CYP3A), may be necessary when used with other drugs that inhibit or induce their metabolic enzymes. Genetic variations of cytochrome P450 2D6 (CYP2D6) and drug-drug interactions causing inhibition (CYP2D6 and/or CYP3A) or induction (CYP3A) may be important for risperidone, and perhaps for aripiprazole, dosing.

Adding inhibitors may cause side effects more easily in drugs with a narrow therapeutic window, such as clozapine or risperidone, than in those with a wide therapeutic window, such as olanzapine or

aripiprazole. Adding inducers may be associated with a gradual development of lost efficacy.” [261]

CYP3A5 genetic polymorphisms in different ethnic populations.

http://www.ncbi.nlm.nih.gov/pubmed/15833928 [282]

“Cyp3A5 activity varies within any given ethnic population, suggesting that genetic variation within the Cyp3A5 gene may be the most important contributor to interindividual and interracial differences in

Cyp3A-dependent drug clearance and response. …Significant differences were observed in the distribution of Cyp3A5*3, Cyp3A5*6, and Cyp3A5*7 alleles among white and African populations. The

frequency of Cyp3A5*3 allele in white Canadians (93%) is higher than in Zimbabweans (77.6%) (p < 0.001). In contrast, Cyp3A5*6 and Cyp3A5*7 alleles are relatively frequent in African subjects (10–22%)

but absent in white subjects (p < 0.001). These differences may reflect evolutionary pressures generated by environmental factors in geographically distinct regions. However, the genetic

polymorphism of Cyp3A5alone does not explain the interindividual differences in Cyp3A mediated metabolism.” [282]

Lurasidone drug-drug interaction studies: a comprehensive review.

http://www.ncbi.nlm.nih.gov/pubmed/24825095 [283]

“Lurasidone PK is altered by strong cytochrome P450 (CYP) 3A4 inhibitors or inducers, and coadministration is contraindicated; whereas moderate CYP3A4 inhibitors have less effect, and lurasidone dosage restrictions are recommended.” [283]

Genomics and pharmacogenomics of schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/20718829 [273]

“Schizophrenia (SCZ) is among the most disabling of mental disorders…SCZ has a heritability estimated at 60-90%. Genetic studies in SCZ have revealed the presence of chromosome anomalies, copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single nucleotide polymorphisms (SNPs) in microRNA genes, mitochondrial

DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the

positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major

substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. About 10-20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the tri-genic cluster integrated by

the CYP2D6+CYP2C19+CYP2C9 genes. The pharmacogenomic response of SCZ patients to conventional psychotropic drugs also depends on genetic variants associated with SCZ-related genes.

Consequently, the incorporation of pharmacogenomic procedures both to drugs in development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system

(CNS) disorders.” [273]

Pharmacogenomics can improve antipsychotic treatment in schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/23606027 [274]

“Schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population, and heritability of up to 80%. Drug therapy is an important approach to treating the disease. However, the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects. Many studies have indicated that nearly 30% of patients exhibit little or no improvements associated with

antipsychotics. The response of individual patients who are given the same dose of the same drug varies considerably. In addition, antipsychotic drugs are often accompanied by adverse drug reactions (ADRs), which can cause considerable financial loss in addition to the obvious societal harm. So, it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity. There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians. Individual differences in drug response is due to a combination of many complex factors including ADEM (absorption, distribution, metabolism, excretion) process, transporting, binding with receptor and intracellular signal transduction. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response. In addition, epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients. In this review, we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes (CYP2D6, CYP1A2, CYP3A4, etc.), drug transporters (mainly ABCB1) and neurotransmitter receptors (dopamine receptors and serotonin receptors, etc.). We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications.” [274]

Pharmacogenomics study in a Taiwan methadone maintenance cohort.

http://www.ncbi.nlm.nih.gov/pubmed/25278738 [284]

“Pharmacogenomics is research to study the drug treatment responses in subgroups of patients according to their genetic variants or genetic expression information. Methadone maintenance treatment, which is usually prescribed for patients with heroin dependence, was launched in Taiwan by the government in 2006. In this study, 366 patients who had taken methadone continually in the

previous 7 days were examined. Data from administration of the Treatment Outcomes Profile (TOP), Severity of Dependence Scale (SDS), Clinical Opioid Withdrawal Scale (COWS), and Treatment

Emergent Symptoms Scale (TESS) were obtained from patients' report records. Genes encoding the liver cytochrome P-450 (CYP) enzymes that are involved with the metabolism of methadone (CYP2B6,

3A4 and 2C19) were selected and genotyped in this cohort. We found that the SNPs on CYP2B6 were associated with plasma S-methadone concentration; SNPs on CYP3A4 were associated with

withdrawal symptoms and side effects; and SNPs on CYP2C19 were associated with methadone dose . SNPs in the genes encoding the morphine phase II metabolic enzyme, UGT2B7, were associated with

withdrawal symptom scores. In pharmacodynamic genes, the SNPs on OPRM1 were associated with insomnia and change in libido side effects. We conclude that SNP markers may be useful for future

methadone dosage adjustment and to reduce adverse reactions.” [284]

The Absence of CYP3A5*3 Is a Protective Factor to Anticonvulsants Hypersensitivity Reactions: A Case-Control Study in Brazilian Subjects.

http://www.ncbi.nlm.nih.gov/pubmed/26291084 [285]

“Although aromatic anticonvulsants are usually well tolerated, they can cause cutaneous adverse drug reactions in up to 10% of patients. The clinical manifestations of the antiepileptic-induced 

hypersensitivity reactions (AHR) vary from mild skin rashes to severe cutaneous drug adverse reactions which are related to high mortality and significant morbidity. Genetic polymorphisms in cytochrome P450 genes are associated with altered enzymatic activity and may contribute to the risk of AHR. Here we present a case-control study in which we genotyped SNPs of CYP2C19, 2C9 and 3A5 of 55 individuals with varying severities of AHR, 83 tolerant, and 366 healthy control subjects from São Paulo, Brazil. Clinical characterization was based on standardized scoring systems and drug patch test. All in vivo investigation followed the ENDA (European Network of Drug Allergy) recommendations. Genotype was determined by real time PCR using peripheral blood DNA as a template. Of all 504 subjects, 65% were females, 45% self-identified as Afro-American, 38% as Caucasian and 17% as having non-African mixed ascendancy. Amongst 55 subjects with AHR, 44 had severe cutaneous drug adverse reactions.

Of the 46 drug patch tests performed, 29 (63%) were positive. We found a strong association between the absence of CYP3A5*3 and tolerant subjects when compared to AHR (p = 0.0002, OR = 5.28

[CI95% 2.09-14.84]). None of our groups presented positive association with CYP2C19 and 2C9 polymorphisms, however, both SNPs contributed to separation of cases and tolerants in a Classification

and Regression Tree. Our findings indicate that drug metabolism genes can contribute in the tolerability of antiepileptics. CYP3A5*3 is the most prevalent CYP3A5 allele associated with reduced enzymatic

function. The current study provides evidence that normal CYP3A5 activity might be a protective factor to aromatic antiepileptics-induced hypersensitivity reactions in Brazilian subjects.” [285]