pazopanib血药浓度个体差异与细胞色素P4503A4基因多态性的关系初探  

Preliminary association of individual different plasma pazopanib concentration with CYP3A4 gene polymorphism

作　　者：吴茂锋 刘畅[1] 戴慧晖 麦长凤 黄丹丽 缪经纬 刘丽忠 方翼 WU Maofeng;LIU Chang;DAI Huihui;MAI Zhangfeng;HUANG Danli;MIAO Jingwei;LIU Lizhong;FANG Yi(PhaseⅠClinical Research Unit,the Sixth Affiliated Hospital of Guangzhou Medical University/Qingyuan People’s Hospital,Qingyuan 511518,Guangdong,China;Department of Pharmacy,Peking University People’s Hospital,Beijing 100044,China)

机构地区：[1]广州医科大学附属第六医院/清远市人民医院药物Ⅰ期临床研究室,广东清远511518 [2]北京大学人民医院药剂科,北京100044

出　　处：《中国临床药理学与治疗学》2020年第12期1376-1380,共5页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：清远市科技计划基金资助项目(DZXQY002);清远市人民医院医学科研基金资助项目(20190208)。

摘　　要：目的:分析健康受试者口服pazopanib片后体内药代动力学(PK)规律,初步探讨pazopanib片PK个体差异的遗传学机制。方法:14例健康男性受试者分别在给药当天单次口服pazopanib片(200 mg)后,采集基线至96 h血液样本,用LC-MS/MS法测定服药后各时间点血药浓度,用WinNonlin 6.3软件计算药代动力学相关参数,采用SNapShot法测定细胞色素P4503A4(CYP3A4)基因多态性。结果:Cmax变化范围(7361.65-26081.00)ng/mL,平均值±标准差(15410.72±6366.21)ng/mL;tmax变化范围(1.50-4.00)h、平均值±标准差(2.50±0.83)h;AUC0-t变化范围(228013.55-775231.63)ng·mL-1·h,平均值±标准差(516279.90±175688.41)ng·mL-1·h。个体间Cmax、AUC相差达3倍以上,tmax可相差2倍以上;14例受试者CYP3A4(RS35599367)位点皆为野生型。结论:pazopanib片在中国健康男性志愿者中个体差异较大,未观察到CYP3A4(rs35599367)位点单核苷酸多态性,pazopanib个体间PK差异可能与其他药物代谢相关基因多态性有关。AIM:To study the pharmacokinetics(PK)of pazopanib tablets and explore the genetic mechanism of individual differences in drug metabolism primarily.METHODS:Fourteen healthy male subjects were respectively administrated with a single dose pazopanib tablet(200 mg)orally on the day of dosing,and their blood samples were collected from baseline to 96 hours.The serum concentration of pazopanib was measured by LC-MS/MS,the parameters of PK were calculated by winnonlin 6.3 software,and the gene polymorphism of cytochrome P4503A4(CYP3A4)was determined by snapshot method.RESULTS:The range of Cmaxwas(7361.65-26081.00)ng/mL,with an average±sd of(15410.72±6366.21)ng/mL;the range of tmaxwas(1.50-4.00)h,with an average±sd of(2.50±0.83)h;AUC0-trange was(228013.55-775231.63)ng·mL-1·h,average±sd was(516279.90±175688.41)ng·mL-1·h;tmax could differ by more than 2 times between individuals,and Cmaxand AUC could differ by more than 3 times.CYP3A4 site(rs35599367)of 14 subjects were all wild-type.CONCLUSION:The pazopanib tablets have large individual differences among Chinese healthy male volunteers,but no CYP3A4(rs35599367)polymorphism differences were observed in this study.Individual PK differences of pazopanib may be related to polymorphisms of other drug metabolism related genes.

关 键 词：PAZOPANIB 细胞色素P4503A4 基因多态性 

分 类 号：R969[医药卫生—药理学]