论文部分内容阅读
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 the potential inhibition and enzyme kinetic parameters of losartan potassium on human liver microsome or recombinant enzyme CYP2C9 and to evaluate the effect of losartan on the area under the plasma concentration-time curve of Gliclazide (AUC )Impact. Methods: The corresponding metabolic rates of losartan potassium (concentration over IC50) and diclofenac sodium (concentration over Km) were determined, and the reversible inhibition type was determined by Dixon plot and Lineweaver-Burk plot Enzyme kinetic inhibition constant Ki. Single-point inactivation was used to determine whether losartan potassium suppresses CYP2C9 on a mechanistic basis. Combined with the Ki value of losartan potassium, other in vivo parameters and the fm value of gliclazide to predict the degree of drug-drug interaction (DDI) in vivo. Results: Dixon mapping and Lineweaver-Burk mapping showed that losartan potassium inhibited the type of CYP2C9 non-competitive inhibition. Losartan potassium in human liver microsomal CYP2C9 and recombinant enzyme CYP2C9 inhibition constant Ki were 16.05 and 53.02μmol·L-1. Losartan potassium does not have a mechanism-based inhibition of CYP2C9. According to the formula, losartan potassium increased the AUC of combined gliclazide by 0.10% or 0.03%. CONCLUSION: Losartan potassium is not easy to cause a large change of Gliclazide AUC under the condition of common clinical dose. However, the combination of two drugs can be extensively used for long-term clinical trials.