title: In vitro assessment of 24 CYP2D6 allelic isoforms on the metabolism of methadone.
abstract: CYP2D6 is an important member of the cytochrome P450 (CYP450) enzyme super family, with at least 100 CYP2D6 alleles being previously identified. Genetic polymorphisms of CYP2D6 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The aim of this study was to clarify the catalytic activities of 24 CYP2D6 alleles on the oxidative in vitro metabolism of methadone. Reactions were incubated with 50-2000  µM methadone for 30 min at 37 °C and terminated by cooling to -80 °C immediately. Methadone and the major metabolite EDDP were analyzed by an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) system. Compared with wild-type CYP2D6*1, most variants showed significantly altered values in Vmaxand intrinsic clearance (Vmax/Km). Only three variants (CYP2D6*88, *91 and E215K) exhibited markedly increased intrinsic clearance values, and one variant CYP2D6*94 showed no significant difference. On the other hand, the kinetic parameters of two CYP2D6 variants (CYP2D6*92 and *96) could not be determined because they had no detectable enzyme activity, whereas 18 variants exhibited significantly decreased values. To sum up, this study demonstrated that more attention should be paid in clinical administration of methadone to individuals carrying these CYP2D6 alleles. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Zhan
authors.affiliation: The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
authors.forename: Ben-Fu
authors.initials: BF
authors.lastname: Wang
authors.affiliation: The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
authors.forename: Si-Cong
authors.initials: SC
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China.
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Dai
authors.affiliation: School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
authors.affiliation: The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
authors.forename: Han
authors.initials: H
authors.lastname: Lin
authors.affiliation: The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
authors.forename: Qing-Quan
authors.initials: QQ
authors.lastname: Lian
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
mesh_terms: D000483:Alleles; D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007313:Insecta; D008691:Methadone / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D020033:Protein Isoforms; D019389:Cytochrome P-450 CYP2D6; D008691:Methadone
keywords: CYP2D6 polymorphism; N-demethylation; allelic variant; drug metabolism; methadone