基于ABCG2基因多态性和肾功能的瑞舒伐他汀群体药动学研究  

Pharmacogenetics-Based Population Pharmacokinetic Analysis of Rosuvastatin in Chinese Patients with Hyperlipidemia:Effects of BCRP Polymorphism and Renal Function

作　　者：赵诗晗 盛长城[2] 陈宇 冒觉蕙 唐才林 黄伟康 张彦燕 白雪 ZHAO Shihan;SHENG Changcheng;CHEN Yu;MAO Juehui;TANG Cailin;HUANG Weikang;ZHANG Yanyan;BAI Xue(College of Pharmacy,Guizhou Medical University,Guiyang 550004,China;Department of Pharmacy,Guizhou Provincial People′s Hospital,Guiyang 550002,China;Guizhou Branch of Shanghai Children′s Medical Center,Shanghai Jiaotong University School of Medicine,Guiyang 550009,China;School of Basic Medicine and Clinical Pharmacy,China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]贵州医科大学药学院,贵阳550004 [2]贵州省人民医院药剂科,贵阳550002 [3]上海交通大学医学院附属上海儿童医学中心贵州医院,贵阳550009 [4]中国药科大学基础医学与临床药学学院,南京211198

出　　处：《中国药学杂志》2025年第5期507-514,共8页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金项目资助(81960681,82260732);中国药学会-施维雅青年医院药学创新研究资助(CPA-B04-ZC-2024-001);2024年药物安全研究项目资助(ADR2024MS15);贵州省人民医院2019年度国家自然科学基金后补助资金资助([2019]GPPH-NSFC-D-2019-25,GPPH-NSFC-2019-26)。

摘　　要：目的本研究旨在建立瑞舒伐他汀在中国高脂血症患者中的群体药动学(PPK)模型,并探讨人口学数据、临床特征和基因多态性(ABCG2、SLCO1B1、SLCO1B3、SLCO10A1、ABCB1、CYP2C9)对该药的药动学参数的影响。方法收集944例患者的944个稳态血药浓度数据,使用超高效液相色谱-串联质谱(UPLC-MS/MS)测定瑞舒伐他汀的血浆浓度,提取DNA并测定浓度,利用Sequenom Mass Array技术平台进行基因分型,最终采用非线性混合效应模型软件(NONMEM)建立模型。结果清除率、表观分布容积和口服吸收常数的群体典型值分别为253 L·h^(-1)、1810 L和0.318 h^(-1)。在相同的剂量下,随着估算肾小球滤过率(eGFR)的降低和rs2199936突变位点的增加,瑞舒伐他汀的稳态浓度升高。携带ABCG2 rs2199936的1个和2个突变位点的个体,其清除率相对于无突变的个体分别降低了32.6%和53.2%。结论ABCG2 rs2199936和eGFR是显著影响瑞舒伐他汀清除率的协变量。对于携带rs2199936突变基因及肾功能不全的患者,应避免使用高剂量瑞舒伐他汀,特别是接受冠状动脉造影的患者。OBJECTIVE To establish a population pharmacokinetic(PK)model for rosuvastatin and investigate the effects of demographic data,clinical characteristics,and genetic polymorphisms(ABCG2,SLCO1B1,SLCO1B3,SLCO10A1,ABCB1,CYP2C9)on its PK parameters in Chinese population.METHODS A total of 944 steady-state concentration data were collected from 944 patients with hyperlipidemia.UPLC-MS/MS was used to determine the plasma concentration of rosuvastatin.DNA was extracted and measured for concentration,and the Sequenom MassArray technology platform was utilized for genetic typing.Eventually a population PK model was established with non-linear mixed-effects modeling software(NONMEM).RESULTS The population estimates for the apparent clearance,apparent volume of distribution and absorption rate constant were 253 L·h^(-1),1810 L and 0.318 h^(-1),respectively.The datasets were best described by a one-compartment model with first-order elimination.The steady-state concentration of rosuvastatin increased as estimated glomerular filtration rate(eGFR)decreased and the variant allele for rs2199936 increased,under the same dosage regimen.Carrying one or two variant alleles for the ABCG2 rs2199936 showed a decrease of 32.6%and 53.2%in apparent clearance relative to the value in individuals without the variant allele.CONCLUSION Both ABCG2 rs2199936 and the eGFR were found to be significant covariates for apparent clearance.The RESULTS suggest that Chinese individuals with renal impairment and one or two variant alleles for the rs21999336 polymorphism(ABCG2)who are undergoing coronary angiography(CAG)should avoid high doses of rosuvastatin.

关 键 词：ABCG2基因 瑞舒伐他汀 群体药动学 中国人群 非线性混合效应模型软件 

分 类 号：R969.1[医药卫生—药理学]