细胞色素P4502D6＊10基因多态性对曲马多药代动力学的影响

Effect of cytochrome P450 2D6＊10 genetic polymorphism on tramadol pharmacokinetics

目的探讨细胞色素P4502D6＊10（CYP2D6＊10）基因多态性对曲马多药代动力学的影响。方法辽宁籍汉族健康志愿者，性别不限，年龄22～45岁，体重50～82kg，身高161～179cm，经左肘静脉采血2ml，采用酚／氯仿抽提法提取全血DNA，采用聚合酶链反应一限制性片段长度多态性进行CYP2D6＊10基因分型，分为野生型纯合子组（w／w组，n=5）、杂合子组（m／w组，n=8）和突变型纯合子组（m／m组．n=6）。右上肢静脉经3min注射曲马多1．5mg／kg。分别于注射前、注射后0．25、0．5、1、1．5、2、3、4、6、8、12、16、24、32h时取血3ml，测定血浆曲马多及O-去甲基曲马多浓度。采用非房室模型方法计算曲马多曲线下面积（AUC0-→∞）、血浆清除率（CL）、血浆消除半衰期（t1/2）、平均滞留时间（MRT）、血浆代谢率（MR）和O-去甲基曲马多峰浓度（Cmax）、达峰时间（Tmax）、AUC0-→∞、MRT。结果与w／w组比较，m／m组曲马多t1/2和MRT延长，MR降低，O-去甲基曲马多AUC0-→∞减少，m／w组曲马多MR降低（P〈0．05或0．01）；与m／m组比较，m/w组曲马多MR降低（P〈0．01）。结论CYP2D6＊10基因多态性是引起曲马多药代动力学个体差异的重要遗传因素之一。

Objective To investigate the effect of cytochrome P450 206＊10 （CYP2D6＊ 10） genetic polymorphism on tramadol phannacokinetics. Methods Nineteen healthy volunteers from Liaoning province aged 22-45 yr weighing 50-82 kg height 161-179 cm were enrolled in this study. Blood samples were taken from left ulnar vein for DNA extraction and CYP2D6＊10 genotyping using phenol chloroform extracting method and polymerase chain reaction-restriction fragment length polymorphism respectively. The volunteers were divided into 3 groups according to their genotypes： wild hemozygote group （w/w）, heterozygote group （m/w） and mutation homozygote group （m/m） . Tramadol 1.5 mg/kg was injected intravenously over 3 rain through a vein in right upper extremity. Blood samples were taken before tramadol injection and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32 h after injection for determination of plasma tramadol and O-demethyl tramadol concentration by highperformance Liquid chromatography. Pharmacokinetic analysis was performed using nonparametric methods. Area under concentration curve （ AUC0-→∞ ） , plasma clearance （CL） , elimination half-life （ t1/2 ） and mean residence time （MRT） and metabolic rate （MR） of tramadol and peak concentration （Cmax） peak time （Tmax）, AUC0-→∞ and MRT of O-demethyl tramadol were calculated. Results MR of tramadol was significantly lower in m/w and m/m group, t1/2 and MRT of tramadol were significantly longer in m/m group and AUC0-→∞of O-demethyl tramadol was significantly lower in m/m group than in w/w group. MR of tramadol was significantly higher in m/w group than in m/m group. Conclusion CYP2D6＊10 genetic polymorphism is one of the genetic factors producing individual variation in tramadol phannacokinetics.