细胞色素P450 CYP2C9＊3对格列本脲和氯诺昔康中国人体药代动力学的影响  

Impact of cytochrome P450 CYP2C9 variant allele CYP2C9·3 on the pharmacokinetics of glibenclamide and lornoxicam in Chinese subjects

作　　者：张逸凡[1] 陈笑艳[1] 郭颖杰[2] 司大勇[2] 周慧[2] 钟大放[1,3] 

机构地区：[1]沈阳药科大学药物代谢与药代动力学实验室 [2]吉林大学生命科学学院 [3]吉林大学生命科学学院,吉林长春130023

出　　处：《药学学报》2005年第9期796-799,共4页Acta Pharmaceutica Sinica

基　　金：国家高技术研究发展计划(863计划)资助项目(2003AA2Z347C).

摘　　要：目的研究人体内细胞色素P4502C9酶突变等位基因CYP2C93对格列本脲和氯诺昔康药代动力学的影响。方法采用PCRRFLP方法对83名无血源关系的受试者进行CYP2C93等位基因的筛查,基因型为CYP2C91/3(n=7)和1/1(n=11)的受试者分别参加了格列本脲和氯诺昔康的人体药代动力学试验。采用LC/MS/MS法分别测定受试者口服格列本脲(2.5mg)和氯诺昔康(8mg)后不同时刻血浆中格列本脲和氯诺昔康的浓度。结果两组受试者口服格列本脲后,CYP2C91/3组AUC0∞显著增加,为CYP2C91/1组的1.5倍,CL/F降低了40%;两组受试者口服氯诺昔康后,CYP2C91/3组AUC0∞亦显著增加,为CYP2C91/1组的2.2倍,CL/F降低了55%。结论CYP2C9酶的突变等位基因CYP2C93对格列本脲和氯诺昔康的药代动力学有显著性影响。Aim To investigate the impact of CYP2C9 ＊ 3 on the pharmacokinetics of glibenclamide and lomoxicam. Methods CYP2C9 ＊ 3 was measured in 83 non-related Chinese subjects by PCR-RFLP. The pharmacokinetics of lomoxicam and glibenelamide were investigated in 18 subjects （7 with CYP2 C9 ＊ 1/＊ 3 genotype and 11 with ＊ 1/＊ 1 genotype）. Glibenclamide and lomoxicam in plasma were determined by the sensitive liquid chromatography-tandem mass spectrometry, separately. Results After a single oral dose of 2.5 mg glibenclamide, Cmax was （70.0 ± 11.5） μg · L^-1 in CYP2C9 ＊ 1/＊ 3 subjects and （51.9 ±12.3） μg · L^-1 in ＊ 1/＊1 subjects. AUC0-∞ were （435 ±47） vs （287 ±95） μg · L^-1（in ＊1/＊3 vs ＊1/＊1 subjects）, and CL/F were （96 ±9.3） vs （160 ±51） mL · min^-1, respectively. Statistic analysis results indicated that glibenclamide AUC0-∞ was significantly higher （ 1.5fold） and subsequently CL/F was significantly lower （40%） in CYP2C9 ＊ 1/＊ 3 subjects than those in ＊ 1/＊ 1 subjects （P 〈 0. 01 ）. After a single oral dose of 8 mg lomoxicam, Cmax was （ 1.54 ± 0. 24） mg·L^-1 in CYP2C9 ＊1/＊3 subjects and （1.19 ±0.37） mg·L^-1 in ＊ 1/＊ 1 subjects. AUC0-∞ were （14.9±2.2） vs （6.92 ± 1.48） mg·hL^-1（in ＊1/＊3 vs ＊ 1/＊ 1 subjects）, and CL/F were（9. 1 ± 1.2 ） vs （ 20. 1 ± 4.6 ） mL ·min^-1, respectively. Statistic analysis results indicated that lornoxicam AUC0-∞ was significantly higher （2. 2-fold ） and subsequently CL/F was significantly lower （55%） in CYP2C9 ＊ 1/ ＊ 3 subjects than those in ＊1/＊1 subjects （P〈0.001）. Conclusion CYP2C9 ＊3 greatly affects both the pharmacokinetic profiles of glibenclamide and lomoxicam. The elimination of these drugs significantly decreased in subjects with CYP2C9 ＊ 1/＊ 3 genotype, especially lomoxicam.

关 键 词：氯诺昔康 格列本脲 细胞色素P450 CYP2C9 药代动力学 遗传多态性 

分 类 号：R963[医药卫生—微生物与生化药学] R969.1[医药卫生—药理学]