细胞色素P4503A5 rs776746位点多态性与培唑帕尼代谢的相关性研究  

Correlation between polymorphism of cytochrome P4503A5 rs776746 locus and pazopanib metabolism

作　　者：吴茂锋 刘秋兰 石碧锐 黄丹丽 麦长凤 陈思静 常惠礼[1] WU Mao-feng;LIU Qiu-lan;SHI Bi-rui;HUANG Dan-li;MAI Zhang-feng;CHEN Si-jing;CHANG Hui-li(PhaseⅠClinical Research Unit,The Sixth Affiliated Hospital of Guangzhou Medical University,Qingyuan People's Hospital,Qingyuan 511518,Guangdong Province,China;Clinical Laboratory,The Sixth Affiliated Hospital of Guangzhou Medical University,Qingyuan People's Hospital,Qingyuan 511518,Guangdong Province,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]广州医科大学附属第六医院、清远市人民医院检验科,广东清远511518

出　　处：《中国临床药理学杂志》2023年第14期2030-2032,共3页The Chinese Journal of Clinical Pharmacology

基　　金：清远市科技计划基金资助项目(221105177684826);清远市人民医院医学科研基金资助项目(20190208,20190210)。

摘　　要：目的探讨细胞色素P4503A5(CYP3A5)基因rs776746位点多态性与培唑帕尼片在健康受试者体内代谢的相关性。方法健康受试者分别于给药前采集血液样本2 mL用于基因多态检测,给药当天单次口服培唑帕尼片(200 mg)后,采集基线至96 h血液样本,用Sanger测序法对CYP3A5基因多态性进行检测,用LC-MS/MS法测定培唑帕尼片的血药浓度,用DAS2.0软件分析计算药代动力学相关参数。结果14例受试者CYP3A5 rs776746位点检测发现A/G基因型与G/G基因型各有7例;A/G基因型组的AUC_(0-t)、AUC_(0-∞)、VRT_(0-t)、VRT_(0-∞)、t_(1/2z)、CL_(z/F)分别为(416417.26±144030.60)ng·mL^(-1)·h,(491965.13±169321.89)ng·mL^(-1)·h,(661.77±44.67)h^(2),(2655.55±1033.54)h^(2),(35.29±5.86)h,(0.45±0.18)mL·h^(-1);G/G基因型组AUC_(0-t)、AUC_(0-∞)、VRT_(0-t)、VRT_(0-∞)、t_(1/2z)、CL_(z/F)分别为(620740.75±163696.52)ng·mL^(-1)·h,(828690.80±241510.66)ng·mL^(-1)·h,(717.14±48.31)h^(2),(5031.35±2161.47)h^(2),(48.13±10.84)h,(0.27±0.10)mL·h^(-1);与A/G基因型受试者相比,G/G基因型受试者的AUC_(0-t)、AUC_(0-∞)上升,且VRT_(0-t)、VRT_(0-∞)、t_(1/2Z)亦增加、CL_(z/F)显著降低,差异均有统计学意义(均P<0.05)。结论CYP3A5基因多态性可能与培唑帕尼片在健康受试者的体内代谢相关。Objective To investigate the relationship between the rs776746 polymorphism of cytochrome P4503A5(CYP3A5)gene and the metabolism of pazopanib tablets in healthy subjects.Methods Blood samples 2 m L were collected from healthy subjects for gene polymorphism detection before administration.After a single oral administration of pazopanib tablets(200 mg)on the day of administration,blood samples were collected from baseline to 96 hours.The gene polymorphism of CYP3A5 was detected by Sanger sequencing method.The plasma concentration of pazopanib tablets was determined by LC-MS/MS method.The pharmacokinetic parameters were analyzed and calculated by DAS 2.0 software.Results Seven cases of A/Ggenotype and seven cases of G/G genotype were detected at rs776746locus of CYP3A5 in 14 subjects.The main parameters of pharmacokinetics in A/G genotype group,AUC_(0-t),AUC_(0-∞),VRT_(0-t),VRT_(0-∞),t_(1/2z)and CL_(z/F)were(416417.26±144030.60)ng·mL^(-1)·h,(491965.13±169321.89)ng·mL^(-1)·h,(661.77±44.67)h^(2),(2655.55±1033.54)h^(2),(35.29±5.86)h,(0.45±0.18)m L·h^(-1),respectively.The main parameter of pharmacokinetics in G/G genotype group,AUC_(0-t),AUC_(0-∞),VRT_(0-t),VRT_(0-∞),t_(1/2z)and CL_(z/F)were(620740.75±163696.52)ng·mL^(-1)·h,(828690.80±241510.66)ng·mL^(-1)·h,(717.14±48.31)h^(2),(5031.35±2161.47)h^(2),(48.13±10.84)h,(0.27±0.10)m L·h^(-1),respectively.Compared with A/G genotype subjects,the AUC_(0-t)and AUC_(0-∞)of G/Ggenotype subjects increased,and VRT_(0-t),VRT_(0-∞),t_(1/2Z)also increased,and CL_(z/F)significantly decreased(P<0.05).Conclusion The polymorphism of CYP3A5 gene may be related to the metabolism of pazopanib tablets in Chinese healthy male volunteers.

关 键 词：培唑帕尼 细胞色素P4503A5 基因多态性 药代动力学 

分 类 号：R97[医药卫生—药品]