Xia Meng-Ming, Wang Li, PAan Pei-Pei, Wang Hai-Yun, Chen Meng-Chun, Chen Yi, Dai Da-Peng, Cai Jian-Ping, Hu Guo-Xin
Pharmazie. 2014 Dec;69(12):898-903.
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 CYP2C91, 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.
CYP2C9是人类细胞色素P450 CYP2C超家族四个已知成员之一，此前已鉴定出至少57个CYP2C9等位基因。CYP2C9的基因多态性显著影响某些药物的疗效和安全性，这可能导致不良反应和治疗失败。本研究的目的是阐明36个CYP2C9等位基因（在中国人群中发现的21个新等位基因，即*36-56）在体外双氯芬酸氧化代谢中的作用。将表达36种人类CYP2C9等位基因的昆虫微粒体与2-100μM双氯芬酸在37℃下孵育30分钟，然后加入30μL 0.1M盐酸终止反应。通过高效液相色谱法（HPLC）分析双氯芬酸及其主要代谢产物4'-羟基（OH）-双氯芬酸。与野生型CYP2C91相比，大多数变体在V(max)、K(m)和内在清除率（V(max)/K(m)）方面显示出显著改变的值。只有一个变体表现出内在清除率值显著增加，而31个变体表现出显著降低的值。因此，本研究表明，在使用双氯芬酸时，应更加关注携带这些CYP2C9等位基因的患者。
