CYP2C9*2基因多态性对CYP3A4野生型健康回族受试者体内的氯沙坦及其活性代谢物E-3174的药动学影响

doi:10.5246/jcps.2018.01.002

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (1): 14-21.DOI: 10.5246/jcps.2018.01.002

CYP2C9*2基因多态性对CYP3A4野生型健康回族受试者体内的氯沙坦及其活性代谢物E-3174的药动学影响

杨璐¹, 郭涛², 庄雪梅³, 顾红燕^1*

1. 首都医科大学附属北京世纪坛医院药剂科临床合理用药生物特征谱学评价北京市重点实验室, 北京 100038
2. 沈阳军区总医院药剂科, 辽宁沈阳 110016
3. 枣庄矿业集团中心医院药学部, 山东枣庄 277800

收稿日期:2017-10-13 修回日期:2017-11-15 出版日期:2018-02-28 发布日期:2017-12-19
通讯作者: Tel.: +86-010-63926034, E-mail: ghyhappycpu@163.com
基金资助:
A Research Grant from the 115 Project of Legionary Medical Treatment and Public Health (Grant No. 06G023).

Influence of CYP2C9*2 genetic polymorphism on pharmacokinetics of losartan and its active metabolite E-3174 on the background of CYP3A4 wild genotype in healthy Chinese Hui subjects

Lu Yang¹, Tao Guo², Xuemei Zhuang³, Hongyan Gu^1*

1. Department of Pharmacy, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing 100038, China
2. Department of Pharmacy, the General Hospital of Shenyang Military Region, Shenyang 110015, China
3. Department of Pharmacy, shandong energy zaozhuang mining group center hospital, Zaozhuang 277800, China

Received:2017-10-13 Revised:2017-11-15 Online:2018-02-28 Published:2017-12-19
Contact: Tel.: +86-010-63926034, E-mail: ghyhappycpu@163.com
Supported by:
A Research Grant from the 115 Project of Legionary Medical Treatment and Public Health (Grant No. 06G023).

摘要/Abstract

摘要：

研究CYP2C9*2基因多态性对CYP3A4野生型健康回族受试者体内的氯沙坦及其活性代谢物E-3174药动学的影响。采用聚合酶链反应-限制性内切酶片段长度多态(Polymerase chain reaction-Restriction fragment length polymorphism, PCR-RFLP)方法检测健康受试者CYP2C9和CYP3A4的基因多态性。在回族受试者中选择8名CYP2C9*1/*1野生型受试者和6名CYP2C9*1/*2突变杂合型受试者, 这14名纳入的受试者均为CYP3A4野生型。单剂量口服氯沙坦钾片剂后采集血样, 使用高效液相-荧光检测方法测定血药浓度。应用DAS 2.0程序估算药动学参数, 包括AUC_0–24、AUC_0–∞、C_max、t_max、CL、V_d和t_1/2, 并采用SPSS16.0软件进行统计分析。CYP2C9*1/*1组E-3174的AUC_0–24、AUC_0–∞和C_max的数值分别为CYP2C9*1/*2组的1.36、1.32和1.64倍, 且差异具有统计学意义(P<0.05)。CYP2C9*2等位基因对氯沙坦的药动学具有显著的影响, 它可以抑制氯沙坦的代谢, 从而导致E-3174的生成减少。然而, 是否需要根据CYP2C9基因多态性来调整临床的给药剂量, 仍需要大样本的临床试验结果来支持。

关键词: 氯沙坦, E-3174, CYP2C9*2, 药动学, 回族

Abstract:

In the present study, we aimed to investigate the influence of CYP2C9*2 genetic polymorphism on pharmacokinetics of losartan and its active metabolite E-3174 on the background of CYP3A4 wild genotype in healthy Chinese Hui subjects. Blood samples were collected from subjects for CYP2C9 and CYP3A4 genotyping using a polymerase chain reaction-restriction fragmentlength polymorphism (PCR-RFLP) assay. A pharmacokinetic study was then carried out in two groups with CYP2C9*1/*1 (n = 8) andCYP2C9*1/*2 (n = 6) genotypes at the same time, and all the 14 subjects were CYP3A4 wildgenotype. Plasma levels of losartan and E-3174 were determined by high-performance liquid chromatography-fluorescence (HPLC-FLD) method before and after a single oral dose of 50-mg dose of losartan in tablet form. The pharmacokinetic parameters were calculated by DAS 2.0 software and analyzed by SPSS 16.0 software. Pharmacokinetic parameters, including area under the curve from 0 h to the last measured point 24 h (AUC_0–24), area under the curve from 0 h to infinite time (AUC_0–∞), peak plasma concentration (C_max), time to reach C_max (t_max), oral clearance (CL), oral volume of distribution (V_d) and elimination half-life (t_1/2), were determined. Compared with the CYP2C9*1/*2 group, the AUC₀_–24, AUC_0–∞ and C_max of E-3174 in CYP2C9*1/*1 group of Hui subjects were respectively 1.36, 1.32 and 1.64 times more, and the statistic differences were significant (P<0.05). The CYP2C9*2 mutant allele played an important role in the pharmacokinetics of losartan after oral administration, and itmight decrease the generationof E-3174. However, large-sample clinical trials are required to validate whether the dose adjustment according to CYP2C9 genotype is necessary.

Key words: Losaran, E-3174, CYP2C9*2, Pharmacokinetics, Hui

中图分类号:

R969.1

Supporting:

杨璐, 郭涛, 庄雪梅, 顾红燕. CYP2C9*2基因多态性对CYP3A4野生型健康回族受试者体内的氯沙坦及其活性代谢物E-3174的药动学影响[J]. 中国药学(英文版), 2018, 27(1): 14-21.

Lu Yang, Tao Guo, Xuemei Zhuang, Hongyan Gu. Influence of CYP2C9*2 genetic polymorphism on pharmacokinetics of losartan and its active metabolite E-3174 on the background of CYP3A4 wild genotype in healthy Chinese Hui subjects[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(1): 14-21.

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CYP2C9*2基因多态性对CYP3A4野生型健康回族受试者体内的氯沙坦及其活性代谢物E-3174的药动学影响

Influence of CYP2C9*2 genetic polymorphism on pharmacokinetics of losartan and its active metabolite E-3174 on the background of CYP3A4 wild genotype in healthy Chinese Hui subjects

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