氯沙坦钾片的生物等效性及CYP2C9*3基因多态性对氯沙坦药代动力学的影响

中国临床药理学与治疗学 ›› 2015, Vol. 20 ›› Issue (2): 175-181.

氯沙坦钾片的生物等效性及CYP2C9^*3基因多态性对氯沙坦药代动力学的影响

陈露露¹, 谭志荣¹, 阳国平², 陈小平¹, 王医成¹, 陈尧¹, 田莹莹¹, 周露萍¹, 王文萍³, 何佳奇³, 周宏灏¹, 欧阳冬生¹

¹中南大学湘雅医院临床药理研究所, 中南大学临床药理研究所,遗传药理学湖南省重点实验室,长沙 410008,湖南;
²中南大学湘雅三医院, 长沙 410013,湖南;
³杭州民生药业有限公司,杭州 310051,浙江

收稿日期:2014-06-21 修回日期:2014-09-16 出版日期:2015-02-26 发布日期:2015-03-20
通讯作者: 欧阳冬生,男,博士,博导,研究方向:遗传药理学与药物基因组学,临床药理学。Tel: 0731-84805380 E-mail: ouyangyj@163.com
作者简介:陈露露,女,硕士研究生,研究方向:遗传药代动力学和药物分析。Tel: 15116282794 E-mail:15116282794@163.com
基金资助:
本项目获国家重大新药创制“十二五”实施计划(2012ZX09303014-001)资助

Bioequivalence of losartan potassium tablets and the influence of CYP2C9^*3 polymorphism on the metabolism of losartan

CHEN Lu-lu¹, TAN Zhi-rong¹, YANG Guo-ping², CHEN Xiao-ping¹, WANG Yi-cheng¹, CHEN Yao¹, TIAN Ying-ying¹, ZHOU Lu-ping¹, WANG Wen-ping³, HE Jia-qi³, ZHOU Hong-hao¹, OUYANG Dong-sheng¹

¹Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics,Changsha 410008, Hunan,China;
²The Third Xiangya Hospital, Central South University; Changsha 410013, Hunan, China;
³Hangzhou Minsheng Pharmaceutical Co. Ltd; Hangzhou 310051, Zhejiang,China

Received:2014-06-21 Revised:2014-09-16 Online:2015-02-26 Published:2015-03-20

摘要/Abstract

摘要： 目的: 评价试验制剂氯沙坦钾片(杭州民生药业)与参比制剂氯沙坦钾片(杭州默沙东制药)的生物等效性及CYP2C9^*3基因多态性对氯沙坦药代动力学的影响。方法: 采用PCR测序法对健康中国汉族受试者CYP2C9^*3(rs1057910 A>C)位点进行基因分型,筛选36名受试者入组本试验,其中CYP2C9^*1/^*1(AA)基因型个体32例,CYP2C9^*1/^*3(AC)基因型个体4例。本研究为两制剂、两周期交叉设计,单次、开放口服给药的单中心试验,给药剂量为氯沙坦钾片(50 mg/片)1片。通过液相色谱-串联质谱法同时测定人血浆中氯沙坦钾及其代谢产物E-3174的浓度,采用DAS3.2.2非房室模型药动学参数计算的方法求算药动学参数。结果: 受试试剂对参比制剂的相对生物利用度分别为氯沙坦(101.5±20.2)%、E-3174(100.0±13.8)%;同CYP2C9^*3为AA基因型受试者相比,AC基因型受试者中氯沙坦的药代动力学参数AUC_0-12、AUC_inf以及C_max升高,其中AUC_0-12、AUC_inf差异有统计学意义;E-3174的药代动力学参数AUC_0-48和AUC_inf降低,不同基因型间差异无统计学意义。结论: 两种制剂生物等效; CYP2C9基因1075A>C突变可导致氯沙坦代谢减慢,但氯沙坦临床剂量可能不需要根据CYP2C9基因型进行调整。

关键词: 氯沙坦钾, 液相色谱-质谱联用, 生物等效性, CYP2C9基因多态性, 药物代谢

Abstract: AIM: To investigate the bioequivalence between losartan potassium tablets (Hangzhou Minsheng Pharmaceutical Co. Ltd) and losartan potassium tablets (Hangzhou MSD)and the influence of CYP2C9^*3 polymorphism on the metabolism of losartan.METHODS: We genotyped CYP2C9^*3 (rs1057910 A>C) sites of Healthy Chinese Han subjects by direct sequencing of PCR products to identify the distribution of CYP2C9^*3 polymorphism. We enrolled 36 subjects in the trial, among which CYP2C9^*1^*1 (AA) genotype were 32 cases and CYP2C9^*1/^* (AC) genotype were 4 cases. This study was designed to be two formulations, two-period crossover, single, open single-center trial of oral administration, the dose of losartan potassium tablets was 1 (50 mg/tablet). We established an HPLC-MS-MS method for the simultaneous determination of losartan and its metabolite E-3174 in human plasma. The pharmacokinetic parameters were calculated by Non-compartmental model using DAS3.2.2 analysis software.RESULTS: The relative bioavailability of two preparations were(101.5±21.5)% (losartan) and (100.0±13.8) % (E-3174); Compared with the AA genotype, AUC_0-12, AUC_inf and C_max of losartan of the AC genotype subjects were higher, and there had a significant difference of AUC_0-12 and AUC_inf; AUC_0-48 and AUC_inf of E-3174 were lower. There had no significant gene-related difference of AUC_0-48 and AUC_inf.CONCLUSION: The two preparations are bioequivalent. The clinical dosage of losartan may not be adjusted based on genotype in spite of CYP2C9 gene 1075A>C mutation slowing down losartan metabolism.

Key words: losartan potassium, LC-MS, bioequivalence, CYP2C9 polymorphism, pharmacokinetics

中图分类号:

R969.1

陈露露, 谭志荣, 阳国平, 陈小平, 王医成, 陈尧, 田莹莹, 周露萍, 王文萍, 何佳奇, 周宏灏, 欧阳冬生. 氯沙坦钾片的生物等效性及CYP2C9^*3基因多态性对氯沙坦药代动力学的影响[J]. 中国临床药理学与治疗学, 2015, 20(2): 175-181.

CHEN Lu-lu, TAN Zhi-rong, YANG Guo-ping, CHEN Xiao-ping, WANG Yi-cheng, CHEN Yao, TIAN Ying-ying, ZHOU Lu-ping, WANG Wen-ping, HE Jia-qi, ZHOU Hong-hao, OUYANG Dong-sheng. Bioequivalence of losartan potassium tablets and the influence of CYP2C9^*3 polymorphism on the metabolism of losartan[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(2): 175-181.

参考文献

[1] Cheung TT, Cheung BM. Managing blood pressure control in Asian patients: safety and efficacy of losartan[J]. Clin Interv Aging, 2014, 19(9): 443-450.
[2] Lo MW, Goldberg MR, McCrea JB, et al. Pharmacokinetics of losartan, an angitens in II receptor antagonist, and its active metabolite EXP3174 in human[J]. Clin Pharmacol Ther, 1995, 58(6): 641-649.
[3] Wang YH, Pan PP, Dai DP, et al. Effect of 36 CYP2C9 variants found in the Chinese population on losartan metabolism in vitro[J]. Xenobiotica, 2014, 44(3): 270-275.
[4] 田自有, 陈赛贞, 徐利君, 等. Rp-HPLC法测定人血浆中氯沙坦钾、厄贝沙坦和格列齐特浓度[J]. 中国临床药学杂志, 2013, 22(4): 230-233.
[5] 韦阳, 黄慧芳, 邵庆翔, 等. 国产氯沙坦钾片的生物等效性研究[J]. 中国临床药理学杂志, 2000,16(2): 106-110.
[6] 周理想, 李相鸿, 孙华, 等. 国产氯沙坦钾胶囊的人体生物等效性研究[J] .中国医药指南, 2012, 10(7): 86-88.
[7] 杨璐, 夏东亚, 郭涛. HPLC-荧光法同时测定人血浆中氯沙坦及其活性代谢物E-3174的浓度[J]. 中国药房, 2009, 20(32): 2509-2911.
[8] 金杰. 健康志愿者氯沙坦钾片的生物等效性研究[J] . 中国医药指南, 2013, 11(2): 3-5.
[9] 马萍, 李鹏飞, 童卫杭, 等. 氯沙坦钾片在健康人体的生物等效性[J]. 中国临床药理学杂志, 2013, 28(3): 179-182.
[10]苑菲, 许剑安, 汪红, 等. LC-MS/MS法测定氯沙坦及其代谢物的血浆浓度及氯沙坦钾片生物等效性评价[J]. 中国临床药学杂志, 2013, 22(1): 13-18.
[11]钟大放, 李高, 刘昌孝. 药物制剂生物利用度和生物等效性试验指导原则(草案)[J]. 药物评价研究, 2011(5): 321-334.
[12]李佐军, 阳国平, 裴奇, 等. 托伐普坦片在中国健康人体的生物等效性研究[J]. 中国临床药理学与治疗学, 2013, 18(9): 1031-1035.
[13]Guo Y, Hu C, He X, et al. Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy[J]. Drug Metab Pharmacokinet, 2012, 27(5): 536-542.
[14]Kurose K, Sugiyama E, Saito Y, et al. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development[J]. Drug Metab Pharmacokinet, 2012, 27(1): 9-54.
[15]张瑾, 陈绍行. 血管紧张肽Ⅱ受体拮抗剂的药动学与临床用药[J]. 中国新药与临床杂志, 2004, 23(2): 111-115.
[16]Bae JW, Choi CI, Lee HI, et al. Effects of CYP2C9^*1/^*3and ^*1/^*13 on the pharmacokinetics of losartan and its active metabolite E-3174[J]. Int J Clin Pharmacol Ther, 2012, 50(9): 683-688.
[17]Yasar U, Forslund-Bergengren C, Tybring G, et al. Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype[J]. Clin Pharmacol Ther, 2002, 71(1): 89-98.