PharmGKB summary

Thorn, Caroline F.; Whirl‐Carrillo, Michelle; Leeder, J. Steven; Klein, Teri E.; Altman, Russ B.

doi:10.1097/fpc.0b013e32834aeedb

Cited by 74 publications

(37 citation statements)

References 35 publications

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“…Genotyping CYP2C9 and VKORC1 aid in the management of patients receiving warfarin therapy [9,10]. CYP2C19 is important for the metabolism of a number of drugs including clopidogrel, omeprazole and phenytoin [11–13]. CYP3A5 is associated with the metabolism of tacrolimus [14].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation

et al. 2017

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BackgroundGenetic determinants of drug response remain stable throughout life and offer great promise to patient-tailored drug therapy. The adoption of pharmacogenetic (PGx) testing in patient care requires accurate, cost effective and rapid genotyping with clear guidance on the use of the results. Hence, we evaluated a 32 SNPs panel for implementing PGx testing in clinical laboratories.MethodsWe designed a 32-SNP panel for PGx testing in clinical laboratories. The variants were selected using the clinical annotations of the Pharmacogenomics Knowledgebase (PharmGKB) and include polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A5 and VKORC1 genes. The CYP2D6 gene allele quantification was determined simultaneously with TaqMan copy number assays targeting intron 2 and exon 9 regions. The genotyping results showed high call rate accuracy according to concordance with genotypes identified by independent analyses on Sequenome massarray and droplet digital PCR. Furthermore, 506 genomic samples across three major ethnic groups of Singapore (Malay, Indian and Chinese) were analysed on our workflow.ResultsWe found that 98% of our study subjects carry one or more CPIC actionable variants. The major alleles detected include CYP2C9*3, CYP2C19*2, CYP2D6*10, CYP2D6*36, CYP2D6*41, CYP3A5*3 and VKORC1*2. These translate into a high percentage of intermediate (IM) and poor metabolizer (PM) phenotypes for these genes in our population.ConclusionGenotyping may be useful to identify patients who are prone to drug toxicity with standard doses of drug therapy in our population. The simplicity and robustness of this PGx panel is highly suitable for use in a clinical laboratory.

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Section: Introductionmentioning

confidence: 99%

Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation

et al. 2017

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“…The dihydrodiol can be converted into catechol or conjugated with glucuronide. Less than 5% of the administered dose of PHT is excreted unchanged in urine [1,2,3,4]. …”

Section: Introductionmentioning

confidence: 99%

“…However, individuals that carry at least one mutated allele have a decrease in the enzyme activity. Those who are heterozygous, carrying one wild-type allele and one mutant allele ( *1/*2 or *1/*3 ) have a mild-to-moderate decrease in the enzyme activity and are classified as IM, whereas the individuals that are homozygous carrying two mutant alleles ( *2/*2 , *2/*3 or *3/*3 ) have a significant decrease in the enzyme activity and are classified as PM [1,16]. …”

Section: Introductionmentioning

confidence: 99%

Role of CYP2C9, CYP2C19 and EPHX Polymorphism in the Pharmacokinetic of Phenytoin: A Study on Uruguayan Caucasian Subjects

Guevara

Maldonado

Uría³

et al. 2017

Pharmaceuticals

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Phenytoin (PHT) oxidative route leads to its main metabolite p-hydroxyphenytoin (p-HPPH), by means of CYP2C9 and CYP2C19. Formation of p-HPPH proceeds via a reactive arene-oxide intermediate. This intermediate can also be converted into PHT dihydrodiol by microsomal epoxide hydrolase (EPHX). The three enzymes are polymorphically expressed and the genetic variants are responsible for changes in the enzyme activity. In order to evaluate the effect that these polymorphisms have on PHT metabolism, PHT and p-HPPH plasma concentrations were measured and the genotype for the three enzymes was assessed in 50 Uruguayan epileptic patients. 30% of the patients were intermediate and 2% were poor metabolizers for CYP2C9, while 20% were intermediate metabolizers for CYP2C19. 44%, 10%, and 46% of subjects had intermediate, increased and decreased activities of EPHX respectively. CYP2C9 was confirmed to be the main responsible enzyme for PHT biotransformation. CYP2C19 seemed to be preponderant in p-HPPH oxidative metabolism. Apart from being responsible for the production of the dihydrodiol metabolite, EPHX also seemed to contribute to pHPPH formation when its activity is low. PHT might be recovered with a decreased activity of EPHX regardless the activity of CYP2C9.

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“…Ethnic distributions of the CYP2C9 polymorphisms are clinically significant in anticoagulation therapy because CYP2C9 is the major P450 that inactivates the active S -enantiomer of warfarin 6 . CYP2C19 catalyzes the metabolism of many commonly used drugs, including omeprazole 11 , phenytoin 12 , and diazepam 13 . Most poor metabolization of CYP2C19 is attributable to the CYP2C19*2 and *3 alleles.…”

Section: Introductionmentioning

confidence: 99%

Combination Analysis in Genetic Polymorphisms of Drug-Metabolizing Enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese Population

Ota¹,

Kamada²,

Hayashida³

et al. 2015

Int. J. Med. Sci.

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The Cytochrome P450 is the major enzyme involved in drug metabolism. CYP enzymes are responsible for the metabolism of most clinically used drugs. Individual variability in CYP activity is one important factor that contributes to drug therapy failure. We have developed a new straightforward TaqMan PCR genotyping assay to investigate the prevalence of the most common allelic variants of polymorphic CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese population. Moreover, we focused on the combination of each genotype for clinical treatment. The genotype analysis identified a total of 139 out of 483 genotype combinations of five genes in the 1,003 Japanese subjects. According to our results, most of subjects seemed to require dose modification during clinical treatment. In the near future, modifications should be considered based on the individual patient genotype of each treatment.

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PharmGKB summary

Cited by 74 publications

References 35 publications

Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation

Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation

Role of CYP2C9, CYP2C19 and EPHX Polymorphism in the Pharmacokinetic of Phenytoin: A Study on Uruguayan Caucasian Subjects

Combination Analysis in Genetic Polymorphisms of Drug-Metabolizing Enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese Population

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