中国人群CYP2D6基因多态性对美托洛尔药代动力学的影响  

Influence of CYP2D6 genetic polymorphism on pharmacokinetics of metoprolol in Chinese population

作　　者：李芹[1] 王睿[2] 郭雅[2] 裴斐[2] 

机构地区：[1]天津医科大学基础医学院药理教研室,天津300070 [2]解放军总医院临床药理药学研究室,北京100853

出　　处：《中国临床药理学与治疗学》2008年第7期796-802,共7页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：国家863计划资助项目(2002AA2Z341L);天津医科大学科学基金资助项目(2007ky06)

摘　　要：目的：研究中国人群CYP2D6基因多态性对美托洛尔药代动力学的影响。方法：使用基因芯片技术测定中国健康志愿者CYP2D6的基因型,按照分型结果将志愿者分为四组,第1组：CYP2D6＊2W＊10W,第2组：CYP2D6＊2H＊10W或CYP2D6＊2M＊10W,第3组：CYP2D6＊2M＊10H,第4组：CYP2D6＊2M＊10M,每组筛选10人,共40人。各组志愿者单次口服100mg美托洛尔后,使用HPLC方法测定血和尿中美托洛尔及其代谢产物α-羟基美托洛尔（HM）的浓度,研究其在不同基因型志愿者体内的药代过程。结果：第2组美托洛尔及其HM的主要药动学参数与第1组相比均没有统计学差异。第3组美托洛尔的t1/2、AUC、Cmax显著高于第1组（P〈0.05）;而HM的t1/2延长47.3%,AUC降低56.0%（P〈0.05）。第4组美托洛尔的t1/2、AUC、Cmax均显著高于第1组（P〈0.05）和第3组（P〈0.05）;HM的t1/2、AUC、Cmax与第1组和第3组相比均有统计学差异（P〈0.05）,且呈现基因剂量效应。第3组和第4组的口服清除率和肾清除率均低于第1组,而0-24h代谢比率分别为第1组的1.82倍和3.96倍。结论：CYP2D6＊2对于美托洛尔的药代动力学过程没有影响;但CYP2D6＊10可降低酶活性,且CYP2D6＊10纯合子变异比杂合子变异对美托洛尔药代动力学的影响更大,呈现基因剂量效应。AIM： To investigate the influence of CYP2D6 genetic polymorphism on pharmacokinetics of metoprolol in Chinese volunteers. METHODS： CYP2D6 genotypes were determined by genechips. Forty adult healthy Chinese volunteers were divided into the following four groups （n = 10 in each group）; Group 1 ： CYP2D6 ＊ 2W ＊ 10W, Group 2：CYP2D6 2H＊ 10W or CYP2D6 ＊ 2M ＊ 10W, Group 3： CYP2D6 ＊ 2M ＊ 10H, Group 4： CYP2D6 ＊ 2M 10M. After oral administration of 100 mg metoprolol, plasma and urine samples were collected from each subject over a 24-h period. The plasma and urine concentrations of metoprolol and its metabolite α-hydroxy metoprolol （HM） were determined by HPLC with fluorescence detection. RESULTS： The main pharmacokinetic parameters of metoprolol and HM in Group 2 were not significantly different from those in Group 1. In Group 3, t1/2, AUC and Cmax of metoprolol were significantly higher than those in Group 1, while t1/2 of HM was 47.3 % longer than that in Group 1 and AUC was 56.0% lower than that in Group 1. In Group 4, t1/2, AUC and Cmax of metoprolol were significantly higher than those in Group I and Group 3, respectively. While for HM, there was a significant difference compared with those in Group 1 and Group 3. The oral clearance and renal clearance in Group 3 and Group d were significantly lower than those in Group 1. The metabolic ratio （ MR0- 24 ） in Group 3 and Group d were 1. 82 and 3.96 times than that in Group 1, respectively. CONCLUSION： The present results show that CYP2D6 ＊ 2 has no influence on the pharmacokinetics of metoproM, but CYP2D6 ＊ 10 reduces CYP2D6 activity which leads to the change of phenotype, and the homozygotes has more significant influence on the pharmacokinetics of metoprolol than the heterozygotes in Chinese population.

关 键 词：CYP2D6 中国人群 美托洛尔 α-羟基美托洛尔 药代动力学 

分 类 号：R969.1[医药卫生—药理学]