title: Effect of CYP2D6 genetic polymorphism on the metabolism of citalopram in vitro.
abstract: Genetic polymorphisms of CYP2D6 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. We aimed at investigating the role of CYP2D6 in the metabolism of citalopram and identifying the effect of 24 CYP2D6 allelic variants we found in Chinese Han population on the metabolism of citalopram in vitro. These CYP2D6 variants expressed by insect cells system were incubated with 10-1000 μM citalopram for 30 min at 37 °C and the reaction was terminated by cooling to -80 °C immediately. Citalopram and its metabolites were analyzed by high-performance liquid chromatography (HPLC). The intrinsic clearance (Vmax/Km) values of the variants toward citalopram metabolites were significantly altered, 38-129% for demethylcitalopram and 13-138% for citalopram N-oxide when compared with CYP2D6*1. Most of the tested rare alleles exhibited significantly decreased values due to increased Km and/or decreased Vmax values. We conclude that recombinant system could be used to investigate the enzymes involved in drug metabolism and these findings suggest that more attention should be paid to subjects carrying these CYP2D6 alleles when administering citalopram in the clinic.
authors.affiliation: Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Ling-Jing
authors.initials: LJ
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fang
authors.affiliation: Department of Nephrology, Beijing Hospital, Ministry of Health, Beijing, China.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Mao
authors.affiliation: Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Zhan
authors.affiliation: Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Li
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: The Key Laboratory of Geriatrics, Beijing Hospital, Beijing Institute of Geriatrics, Ministry of Health, Beijing, China. Electronic address: caijp61@vip.sina.com.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
authors.affiliation: Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: hgx@wmu.edu.cn.
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
mesh_terms: D055162:Biocatalysis; D015283:Citalopram / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D015283:Citalopram; D019389:Cytochrome P-450 CYP2D6
keywords: Citalopram; Cytochrome P450 2D6; Drug metabolism; Enzymatic activity; Fluorescence; Genetic polymorphism