中国人群CYP2D6基因多态性对美托洛尔药代动力学的影响

中国临床药理学与治疗学 ›› 2008, Vol. 13 ›› Issue (7): 796-802.

中国人群CYP2D6基因多态性对美托洛尔药代动力学的影响

李芹^1,2, 王睿², 郭雅², 裴斐²

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

收稿日期:2008-03-28 修回日期:2008-06-23 出版日期:2008-07-26 发布日期:2020-10-14
通讯作者: 王睿,女,研究员,博士生导师,主要从事临床药理学研究。Tel:010-66939409 E-mail:wangrui301@vip.sina.com
作者简介:李芹,女,博士,讲师,主要从事临床药理学研究。Tel:022-23542523 E-mail:liqinql@163.com
基金资助:
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)

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

LI Qin^1,2, WANG Rui², GUO Ya², PEI Fei²

¹Department of Pharmacology, Tianjin Medical University, Tianjin 300070, China;
²Department of Clinical Pharmacology, Chinese PLA General Hospital, Beijing 100853, China

Received:2008-03-28 Revised:2008-06-23 Online:2008-07-26 Published:2020-10-14

摘要/Abstract

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t_1/2、AUC、C_max显著高于第1组(P<0.05);而HM的t_1/2延长47.3%,AUC降低56.0%(P<0.05)。第4组美托洛尔的t_1/2、AUC、C_max均显著高于第1组(P<0.05)和第3组(P<0.05);HM的t_1/2、AUC、C_max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。

关键词: CYP2D6, 中国人群, 美托洛尔, α-羟基美托洛尔, 药代动力学

Abstract: 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 andHM in Group 2 were not significantly different from those in Group 1.In Group 3, t_1/2, AUC and C_max of metoprolol were significantly higher than those in Group 1, while t_1/2 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, t_1/2, AUC and C_max of metoprolol were significantly higher than those in Group 1 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 4 were significantly lower than those in Group 1.The metabolic ratio (MR_0-24) in Group 3 and Group 4 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 metoprolol, 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.

Key words: CYP2D6, Chinese population, metoprolol, α-hydroxy metoprolol, pharmacokinetics

中图分类号:

R969.1
R285

李芹, 王睿, 郭雅, 裴斐. 中国人群CYP2D6基因多态性对美托洛尔药代动力学的影响[J]. 中国临床药理学与治疗学, 2008, 13(7): 796-802.

LI Qin, WANG Rui, GUO Ya, PEI Fei. Influence of CYP2D6 genetic polymorphism on pharmacokinetics of metoprolol in Chinese population[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(7): 796-802.

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