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      Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC®) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update

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          Abstract

          CYP2D6 and CYP2C19 polymorphisms affect the exposure, efficacy and safety of tricyclic antidepressants (TCAs), with some drugs being affected by CYP2D6 only (e.g., nortriptyline and desipramine) and others by both polymorphic enzymes (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine). Evidence is presented for CYP2D6 and CYP2C19 genotype-directed dosing of TCAs. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants.

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          Most cited references25

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

          Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, 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).
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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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              A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants.

              Many drugs, including proton pump inhibitors and certain antidepressants, are metabolized by the polymorphic cytochrome P450 (CYP) 2C19 enzyme. A significant portion of extensive metabolizers do not reach appropriate drug levels, and our objective was to investigate any genetic background. The 5'-flanking region of the CYP2C19 gene from subjects with rapid omeprazole metabolism was sequenced, and CYP2C19 phenotype-genotype associations were analyzed in Swedish (n = 107) and Ethiopian (n = 126) extensive metabolizers. The relationship of the metabolic ratio of omeprazole (omeprazole/5-hydroxyomeprazole in plasma 3 hours after drug intake) with the area under the plasma concentration-time curve was used for prediction studies. Electrophoretic mobility shift assays were conducted by use of human nuclear protein extracts. Hepatic reporter vector transfections were carried out in CD1 mice. We identified a novel allele (CYP2C19*17) carrying -806C>T and -3402C>T, with a frequency of 18% in both Swedes and Ethiopians and 4% in Chinese subjects. In Swedes the metabolic ratio of omeprazole was higher in subjects homozygous for CYP2C19*1 (median, 0.50 [interquartile range, 0.37-0.73]) than in those homozygous for CYP2C19*17 (median, 0.25 [interquartile range, 0.15-0.33]) (P = .010). In Ethiopians a similar difference in the S/R-mephenytoin ratio was observed between individuals homozygous for CYP2C19*1 (median, 0.20 [interquartile range, 0.12-0.37]) and those homozygous for CYP2C19*17 (median, 0.05 [interquartile range, 0.03-0.06]) (P = .013). Electrophoretic mobility shift assays showed specific binding of human hepatic nuclear proteins to an element carrying -806T but not -806C. Reporter vector experiments showed an increased transcriptional activity of the CYP2C19*17 allele in vivo in mice. Predictions revealed that CYP2C19*17 homozygotes would attain 35% to 40% lower omeprazole area under the plasma concentration-time curve values than subjects homozygous for CYP2C19*1 taking standard doses of omeprazole. CYP2C19*17 is likely to cause therapeutic failures in drug treatment with, for example, proton pump inhibitors and antidepressants.
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                Author and article information

                Journal
                0372741
                3058
                Clin Pharmacol Ther
                Clin. Pharmacol. Ther.
                Clinical pharmacology and therapeutics
                0009-9236
                1532-6535
                27 January 2017
                13 February 2017
                July 2017
                20 June 2018
                : 102
                : 1
                : 37-44
                Affiliations
                [1 ]DeBartolo Family Personalized Medicine Institute, Division of Population Science, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
                [2 ]Department of Genetics, Stanford University, Stanford, California, USA
                [3 ]Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
                [4 ]Department of Clinical, Social and Administrative Sciences, College of Pharmacy, and Department of Psychiatry, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
                [5 ]Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
                [6 ]Department of Psychiatry, Dokkyo Medical University, Japan
                [7 ]Department of Experimental and Clinical Pharmacology, College of Pharmacy, and Department of Psychiatry, College of Medicine, University of Minnesota, Minneapolis, MN, USA
                [8 ]Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, USA
                [9 ]Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
                [10 ]Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children’s Mercy-, Kansas City, Missouri and Department of Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri, USA
                [11 ]Center for Molecular Medicine, NorthShore University HealthSystem, Evanston, IL, USA
                [12 ]Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
                [13 ]Division of Research, Federal Institute of Drugs and Medical Devices, Bonn, Germany
                Author notes
                Corresponding Author: Julia C. Stingl, MD, Division of Research, Federal Institute of Drugs and Medical Devices And University of Bonn Medical School, Kurt-Georg-Kiesinger-Allee 3, D-53175 Bonn, Germany, Phone: +49 (0)228-99-307-3570, Julia.Stingl@ 123456bfarm.de
                Article
                PMC5478479 PMC5478479 5478479 nihpa836790
                10.1002/cpt.597
                5478479
                27997040
                29d97c70-f34d-454c-9f20-3de24fc84adf
                History
                Categories
                Article

                desipramine,and trimipramine,CYP2D6,CYP2C19,pharmacogenetics,tricyclic antidepressants,amitriptyline,clomipramine,doxepin,imipramine,nortriptyline

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