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Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

Authors Fang P, Zheng X, He JY, Ge HL, Tang PF, Cai JP, Hu GX

Received 3 February 2017

Accepted for publication 30 March 2017

Published 21 April 2017 Volume 2017:11 Pages 1283—1290


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Qiongyu Guo

Ping Fang,1 Xiang Zheng,1 Jiayang He,1 Honglei Ge,1 Pengfei Tang,1 Jianping Cai,2 Guoxin Hu1

1Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, 2The Ministry of Health (MOH) Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, People’s Republic of China

Background: Cytochrome P450 2D6 (CYP2D6), a member of the CYP450 enzyme super family, is a polymorphic enzyme that metabolizes ~25% of therapeutic drugs. CYP2D6 exhibits significant genetic polymorphisms which might cause adverse effects and therapeutic failures of some drugs.
Objective: The purpose of this study was to evaluate the catalytic activities of 22 novel CYP2D6 alleles (CYP2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, *96, *97, *98, R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C) on the metabolism of gefitinib in vitro.
Methods and results: CYP2D6 variants were incubated with 1–100 µM gefitinib for 60 min at 37°C and the reaction was terminated by cooling to -80°C immediately. Gefitinib and its metabolite O-desmethyl gefitinib were analyzed by an ultra-performance liquid chromatography-tandem mass spectrometry system. Compared to CYP2D6.1, most CYP2D6 variants exhibited significantly decreased relative clearance values (from 3.11% to 79.35%), whereas CYP2D6.92 and CYP2D6.96 displayed no detectable enzyme activity. Only CYP2D6.94 exhibited a markedly increased intrinsic clearance value, and eight variants (CYP2D6.88, CYP2D6.89, CYP2D6.91, CYP2D6.97, V342M, R344Q, F219S, and F164L) showed no significant difference. In addition, 23 CYP2D6 allelic isoforms exhibited substrate inhibition trend toward gefitinib.
Conclusion: As the first study of all the aforementioned alleles for gefitinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism of gefitinib, and may also offer a reference for personalized treatment with gefitinib in clinical settings.

Keywords: CYP2D6, genetic polymorphism, drug metabolism, gefitinib, enzymatic activity, personalized treatment, NSCLC

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