CYP3A酶突变类型与舒芬太尼代谢的性别差异研究  

Mutation types of CYP3A enzymes and sex differences in sufentanil metabolism

作　　者：蒋颖 秦志刚 冯力元 刘冠磊 黎洁钰 刘先哲 李勇帅 陈妍 李鹏[2] 顾健腾 JIANG Ying;QIN Zhigang;FENG Liyuan;LIU Guanlei;LI Jieyu;LIU Xianzhe;LI Yongshuai;CHEN Yan;LI Peng;GU Jianteng(Department of Anaesthesiology,First Affiliated Hospital,Faculty of Pharmacy and Laboratory Medicine,Army Medical University(Third Military Medical University),Chongqing,China;Department of Pharmacognosy and Traditional Chinese Pharmacy,Faculty of Pharmacy and Laboratory Medicine,Army Medical University(Third Military Medical University),Chongqing,China)

机构地区：[1]陆军军医大学(第三军医大学)第一附属医院麻醉科,重庆 [2]陆军军医大学(第三军医大学)药学与检验医学系生药学与中药学教研室,重庆

出　　处：《陆军军医大学学报》2025年第6期581-590,共10页Journal of Army Medical University

基　　金：重庆英才项目基金(CQYC20220303588)。

摘　　要：目的 基于细胞色素P450 3A(cytochrome P450 3A,CYP3A)酶突变类型,探究舒芬太尼在中国患者体内药物代谢的性别差异。方法 将中国人群细胞色素P450 3A4基因*1G位点(cytochrome P450 3A4 gene*1G locus,CYP3A4*1G)和细胞色素P450 3A5基因*3位点(cytochrome P4503A5 gene*3 locus,CYP3A5*3)突变组合可能导致的影响程度赋予不同权重,依据CYP3A酶突变程度将患者分为3类:Ⅰ类人群,CYP3A4*1G/*1G基因型或CYP3A4*1/*1G+CYP3A5*3/*3基因型;Ⅱ类人群,CYP3A4*1/*1G+CYP3A5*1/*3基因型;Ⅲ类人群,CYP3A4*1/*1基因型或CYP3A4*1/*1G+CYP3A5*1/*1基因型。研究采用单剂量、双盲、分层随机抽样设计,共纳入陆军军医大学第一附属医院255名腔镜手术患者,独立的统计学家根据术前基因检测结果将患者分类,采用分层随机抽样的方式从每类各抽取30人构成研究队列(每组男女比例1:1),并随机命名各组为A、B或C组。临床研究人员和受试者对分组结果、基因检测结果双盲。90名患者入室后接受单剂量舒芬太尼诱导,于给药前2 min和给药后2~120 min内共10个时间点采集血样。术后测定血浆药物浓度,计算药代动力学参数,比较同一群体内不同性别患者的药物代谢差异并揭盲。结果 队列符合二房室药代动力学模型,揭盲A、B、C组分别对应Ⅰ、Ⅱ、Ⅲ类人群。在不同CYP3A酶突变程度的患者群体内,女性各时间点的血药浓度-时间曲线均低于男性,女性的总清除率更高(P≤0.01),0~∞时的药时曲线下面积更小(P<0.05)。此外,Ⅰ类人群中女性的中央室消除速率和药物自中央室的分布速率较男性更大(P<0.05),男性的药物分布半衰期(P<0.05)和消除半衰期(P<0.01)更长。Ⅱ、Ⅲ类人群中男性的药时曲线下总面积均大于女性(P<0.05)。结论 舒芬太尼在中国患者体内的药物代谢具有性别差异,女性体内舒芬太尼分布与消除均快于男性,男性患者体内的药物暴露程度更高。术前CYP3A酶基�Objective To explore the sex differences in drug metabolism of sufentanil in Chinese patients based on the mutation classification of cytochrome P4503A(CYP3A)enzymes.Methods According to the possible effects of combined cytochrome P4503A4 gene*1G locus(CYP3A4*1G)and cytochrome P4503A5 gene*3 locus(CYP3A5*3)mutation groups on Chinese population,we added different weights to CYP3A4*1G and CYP3A5*3 polymorphisms and classified patients into 3 groups:GroupⅠ,patients carried either the CYP3A4*1G/*1G allele or both CYP3A4*1/*1G allele and CYP3A5*3/*3 allele;GroupⅡ,patients with both CYP3A4*1/*1G allele and CYP3A5*1/*3 allele;GroupⅢ,patients with either the CYP3A4*1/*1 allele or both CYP3A4*1/*1G allele and CYP3A5*1/*1 allele.A single-dose,double-blind,stratified random sampling was performed,and 255 patients undergoing endoscopic surgery in the First Affiliated Hospital of Army Medical University were finally subjected.According to the results of genetic testing,an independent statistician,before operation,randomly selected 30 patients from each stratified group to form a study cohort(male-female ratio of 1∶1)and named each group A,B or C.Clinical investigators and subjects kept double-blind to the results of grouping and genetic testing.After entering the operating room,the subjected 90 patients received a single dose of sufentanil followed by collection of blood samples at 10 time points including 2 min before and from 2 to 120 min after administration.After the surgery,we determined the plasma drug concentration,calculated the pharmacokinetic parameters,and compared the metabolic differences between different genders in each group and unblinded the study.Results The cohort best fitted the two-compartment pharmacokinetic model,and groups A,B and C corresponded to groupⅠ,ⅡandⅢ,respectively.In different patient groups based on mutatron types of CYP3A enzymes the females had lower plasma drug concentration-time curves at each time point,higher systemic clearance(P≤0.01)and smaller area under the plasma c

关 键 词：性别差异 CYP3A 舒芬太尼 药物代谢 基因突变 

分 类 号：R394.6[医药卫生—医学遗传学] R969.1[医药卫生—基础医学] R971.1