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      Impact of CYP2D6 Functional Allelic Variations on Phenoconversion and Drug-Drug Interactions

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          Abstract

          We investigated whether CYP2D6 extensive metabolizers carrying a nonfunctional allele are at higher risk of phenoconversion to poor metabolizers in the presence of CYP2D6 inhibitors. Seventeen homozygous carriers of two fully-functional alleles and 17 heterozygous carriers of one fully-functional and one nonfunctional allele participated in this trial. Dextromethorphan 5 mg and tramadol 10 mg were given at each of the three study sessions. CYP2D6 was inhibited by duloxetine 60 mg (session 2) and paroxetine 20 mg (session 3). A higher rate of phenoconversion to intermediate metabolizers with duloxetine (71% vs. 25%, P = 0.009) and to poor metabolizers with paroxetine (94% vs. 56%, P = 0.011) was observed in heterozygous than homozygous extensive metabolizers. The magnitude of drug-drug interaction between dextromethorphan and paroxetine was higher in homozygous than in heterozygous subjects (14.6 vs. 8.5, P < 0.028). Our study suggests that genetic extensive metabolizers may not represent a homogenous population and that available genetic data should be considered when addressing drug-drug interactions in clinical practice.

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          Most cited references 29

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          The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype.

          Inferring CYP2D6 phenotype from genotype is increasingly challenging, considering the growing number of alleles and their range of activity. This complexity poses a challenge in translational research where genotyping is being considered as a tool to personalize drug therapy. To simplify genotype interpretation and improve phenotype prediction, we evaluated the utility of an "activity score" (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African-American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Phenotype prediction, given as a probability for each AS group, was most accurate if ethnicity was considered; among subjects with genotypes containing a CYP2D6*2 allele, CYP2D6 activity was significantly slower in African Americans compared to Caucasians. The AS tool warrants further prospective evaluation for CYP2D6 substrates and in additional ethnic populations.
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            Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update.

            Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.
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              Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants.

              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.
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                Author and article information

                Journal
                Clinical Pharmacology & Therapeutics
                Clin. Pharmacol. Ther.
                Wiley
                00099236
                November 06 2017
                Affiliations
                [1 ]Division of Clinical Pharmacology and Toxicology; Geneva University Hospitals; Geneva Switzerland
                [2 ]Geneva-Lausanne School of Pharmacy; University of Geneva; Geneva Switzerland
                [3 ]Unit of Toxicology, CURML; Lausanne-Geneva Switzerland
                [4 ]Swiss Center for Applied Human Toxicology; Geneva Switzerland
                [5 ]Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne; Lausanne Switzerland
                [6 ]Faculty of Medicine, University of Geneva; Geneva Switzerland
                Article
                10.1002/cpt.889
                28940476
                987c002b-6d76-42ab-b26d-f45c88b2cc30
                © 2017

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