ABCB1、HLA-B* 1502、EPHX1基因多态性对卡马西平在健康人体内药代动力学特征的影响  

Effects of ABCB1, HLA-B * 1502 and EPHX1 genetic polymorphisms on carbamazepine pharmacokinetics in healthy subjects

作　　者：穆洪丽 解染 史革鑫 赵侠[3] 赵恒利 张继国 温清 MU Hong-li;XIE Ran;SHI Ge-xin;ZHAO Xia;ZHAO Heng-li;ZHANG Ji-guo;WEN Qing(Department of Pharmacy,Shandong First Medical University,Shandong Academy of Medical Sciences,Tai'an 271000,Shandong Province,China;Department of Clinical Research Center,Central Hospital Affiliated to Shandong First Medical University,Jinan 250013y Shandong Province,China;Department of Pharmacy,Peking University First Hospital,Beijing 100034,China)

机构地区：[1]山东第一医科大学山东省医学科学院药学院,山东泰安271000 [2]山东第一医科大学附属中心医院临床研究中心,山东济南250013 [3]北京大学第一医院药学部,北京100034

出　　处：《中国临床药理学杂志》2022年第9期979-983,共5页The Chinese Journal of Clinical Pharmacology

基　　金：国家科技重大专项基金资助项目(2017ZX09101001);国家科技重大专项基金资助项目(2020ZX09201025)。

摘　　要：目的研究卡马西平治疗相关基因ABCB1、HLA-B*1502、EPHX1基因多态性位点对卡马西平在健康人体内药代动力学特征的影响。方法研究纳入36例健康受试者,单次空腹服用卡马西平片100 mg,用药后72 h内采集外周静脉血。用LC-MS/MS法测定卡马西平血药浓度,用WinNonlin 8.1计算其药代动力学参数;用一代Sanger测序法对ABCB1、HLA-B*1502、EPHX1基因多态性位点进行检测分型,并统计分析卡马西平在各基因型健康受试者体内代谢特征的差异。结果空腹使用卡马西平后,ABCB1(rs1045642)野生型(GG)和突变型(AA)受试者的主要药动参数Tmax分别为3.50和2.63 h;t_(1/2)分别为(54.11±15.10)和(59.22±16.19)h;AUC0-72 h分别为(45.04±7.25)和(48.84±3.73)ng·L^(-1)·h^(-1);C_(max)分别为(1058.87±97.97)和(1152.60±74.76)ng·mL^(-1);在不同基因型间,Tmax、Cmax的差异有统计学意义(P<0.05),AUC_(0-72)h、t_(1/2)的差异无统计学意义(P>0.05)。HLA-B*1502(rs2844682)野生型(GG)和突变型(GA)受试者Tmax分别为2.75和2.00 h;t_(1/2)分别为(51.75±13.52)和(68.53±18.70)h;AUC0-72 h分别为(45.50±6.15)和(49.84±5.14)ng·L^(-1)·h^(-1);C_(max)分别为(1100.96±101.60)和(1155.12±88.97)ng·mL^(-1);不同基因型间,t1/2的差异有统计学意义(P<0.05),T_(max)、C_(max)、AUC_(0-72)h的差异无统计学意义(P>0.05)。EPHX1(rs1051740)野生型(TT)和突变型(CC)受试者Tmax分别为2.50和2.00 h;t_(1/2)分别为(49.38±13.39)和(63.97±22.20)h;AUC0-72 h分别为(43.53±5.75)和(49.63±5.26)ng·L^(-1)·h^(-1);C_(max)分别为(1076.24±80.90)和(1188.38±73.94)ng·mL^(-1)·h^(-1);不同基因型间,Cmax与AUC_(0-72)h差异有统计学意义(P<0.05),Tmax、t_(1/2)的差异无统计学意义(P>0.05)。结论ABCB1、HLA-B*1502、EPHX1可显著影响卡马西平体内药代动力学过程,是卡马西平体内代谢差异的重要遗传因素。Objective To study the effect of polymorphic loci of carbamazepine therapeutic-related genes ABCB1,HLA-B*1502 and EPHX1 on the pharmacokinetic characteristics of carbamazepine in healthy volunteers.Methods Thirty-six healthy subjects were enrolled in this study.They were given carbamazepine tablets 100 mg once in fasting state.Peripheral venous blood was collected within 72 h after administration,and plasma concentration of carbamazepine was determined by LC-MS/MS.The polymorphism loci of ABCB1,HLA-B*1502 and EPHX1 were detected and classified by first-generation Sanger sequencing method,and the pharmacokinetic difference of carbamazepine in healthy subjects with different genotypes were analyzed statistically.Results After carbamazepine on an empty stomach,the main pharmacokinetic parameters of ABCB1(rs1045642)wild-type(GG)and mutant(AA)subjects were T_(max)3.50 and 2.63 h,respectively;t_(1/2)(54.11±15.10)and(59.22±16.19)h;AUC_(0-72)h(45.04±7.25)and(48.84±3.73)h·ng·L^(-1);Cmax(1058.87±97.97)and(1152.60±74.76)ng·mL^(-1);there were statistically significant differences in T_(max)and Cmaxamong different genotypes(P<0.05),and there was no significant difference in AUC_(0-72)hand t_(1/2)among different genotypes(P>0.05).The T_(max)of HLA-B*1502(rs2844682)wild-type(GG)and mutant(GA)subjects were 2.75 and 2.00 h,respectively;t_(1/2)were(51.75±13.52)and(68.53±18.70)h,respectively;AUC_(0-72)hwere(45.50±6.15)and(49.84±5.14)h·ng·L^(-1);Cmaxwere(1100.96±101.60)and(1155.12±88.97)ng·mL^(-1),respectively;there were significant differences in t_(1/2)among different genotypes(P<0.05),but there was no significant difference in T_(max),C_(max)and AUC_(0-72)hamong different genotypes(P>0.05).The T_(max)of EPHX1(rs1051740)wild-type(TT)and mutant(CC)subjects were 2.50 and2.00 h,respectively;t_(1/2)were(49.38±13.39)and(63.97±22.20)h,respectively;AUC_(0-72)hwere(43.53±5.75)and(49.63±5.26)h·ng·L^(-1);Cmaxwere(1076.24±80.90)and(1188.38±73.94)h·ng·mL^(-1),respectively;there were significant differences in Cmaxa

关 键 词：卡马西平 ABCB1基因 HLA-B*1502基因 EXPH1基因 基因多态性 药代动力学 

分 类 号：R97[医药卫生—药品]