title: The role of CYP2C9 genetic polymorphisms in the oxidative metabolism of diclofenac in vitro.
abstract: CYP2C9 is one of four known members of the human cytochrome P450 CYP2C superfamily, with at least 57 CYP2C9 alleles being previously identified. Genetic polymorphisms of CYP2C9 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The purpose of the present study was to clarify the role of 36 CYP2C9 alleles, 21 novel alleles (*36-*56) found in the Chinese population, in the oxidative metabolism of diclofenac in vitro. Insect microsomes expressing the 36 human CYP2C9 alleles were incubated with 2-100 μM diclofenac for 30 min at 37 degrees C and terminated by the addition of 30 μL 0.1 M HCl. Diclofenac and 4'-hydroxyl (OH)-diclofenac, the major diclofenac metabolite, were analyzed by high-performance liquid chromatography (HPLC). Compared with wild-type CYP2C9*1, most variants showed significantly altered values in V(max), K(m) and intrinsic clearance (V(max)/K(m)). Only one variant exhibited markedly increased intrinsic clearance value, whereas 31 variants exhibited significantly decreased values. Thus, this study demonstrated that more attention should be given to subjects carrying these CYP2C9 alleles when administering diclofena.
authors.forename: Meng-Ming
authors.initials: MM
authors.lastname: Xia
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: PAan
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Wang
authors.forename: Meng-Chun
authors.initials: MC
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Dai
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D002460:Cell Line; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism*; D004008:Diclofenac / Q000493:pharmacokinetics*; D006801:Humans; D007313:Insecta / Q000378:metabolism; D007700:Kinetics; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011994:Recombinant Proteins; D004008:Diclofenac; D065729:Cytochrome P-450 CYP2C9