基于体外CYP2C9抑制数据定量预测体内氯沙坦钾-格列齐特的相互作用  

Quantitative prediction of in vivo losartan-gliclazide interactions based on in vitro inhibition data for CYP2C9

作　　者：林利芬[1] 田自有[1] 陈赛贞[1] 陈青华[1] 董爱琴[1] 尤君芬[1] 夏哲林 林佳苗 

机构地区：[1]台州市中心医院药剂科,浙江台州318000

出　　处：《中国医院药学杂志》2015年第12期1067-1071,共5页Chinese Journal of Hospital Pharmacy

基　　金：浙江省药学会医院药学专项科研基金项目(编号:2010ZYY22);台州市科技局项目(编号:102KY10-5)

摘　　要：目的:考察氯沙坦钾对人肝微粒体或重组酶CYP2C9的潜在抑制和酶动力学参数,并通过预测模型评估氯沙坦钾对格列齐特的血药浓度-时间曲线下面积(AUC)的影响。方法:采用不同浓度的氯沙坦钾(浓度跨越IC50)和底物双氯芬酸钠(浓度跨越Km值)测定出相应的代谢速率,用Dixon作图和Lineweaver-Burk作图来判断可逆抑制类型,计算酶动力学抑制常数Ki。单点失活法测定氯沙坦钾对CYP2C9是否基于机制性的抑制。结合氯沙坦钾的Ki值、其他体内参数和格列齐特的fm值来预测体内产生药物-药物相互作用(DDI)的程度。结果:通过Dixon作图和Lineweaver-Burk作图,表明氯沙坦钾对CYP2C9的抑制类型属于非竞争性抑制。氯沙坦钾对人肝微粒体中CYP2C9和重组酶CYP2C9的抑制常数Ki分别为16.05和53.02μmol·L-1。氯沙坦钾对CYP2C9不存在基于机理性的抑制。根据公式计算,氯沙坦钾可使联用的格列齐特的AUC增加0.10%或0.03%。结论:氯沙坦钾在临床常用的剂量条件下,不易引起格列齐特AUC较大的变化,但两药能否广泛地联合应用,有待长期的临床实验来验证。OBJECTIVE To investigate potential inhibitory effects and enzyme kinetic parameters of losartan potassium on human liver microsomes and recombinant enzyme CYP2C9,and evaluate effects of losartan potassium on area under concentration-time curve（AUC） of gliclazide. METHODS Different concentrations of losartan potassium（concentrations across IC50） and diclofenac sodium（concentrations across Kmvalue） were used to determine corresponding metabolic rate. Dixon and Lineweaver-Burk plots were used to determine reversible inhibition type and inhibition kinetics parameters of Ki. Single point inactivation experiments were used to determine potential mechanism-based inhibition of losartan potassium towards CYP2C9. In vivo drug-drug interaction（ DDI） magnitude was predicted using Ki,other parameters of losartan potassium and fmof gliclazide. RESULTS Both Dixon and Lineweaver-Burk plots demonstrated that inhibition of CYP2C9 by losartan potassium was the best fit for noncompetitive inhibition,and Kivalues were calculated to be 16. 05 and 53. 02 μmol·L^-1for CYP2C9 of human liver microsomes and recombinant enzyme,respectively. Losartan potassium showed no mechanism-based inhibition effects against CYP2C9. Losartan potassium increased AUC of gliclazide by 0. 1% or0. 03%. CONCLUSION Losartan potassium with clinical therapeutic dose,is not easy to induce significant changes of AUC of gliclazide. Whether combination of these two drugs can be extensively used needs to be confirmed by clinical experiment.

关 键 词：氯沙坦钾 格列齐特 CYP2C9 相互作用 体外预测 

分 类 号：R969.2[医药卫生—药理学]