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

发布时间：2018-02-08 14:11

本文关键词： 氯沙坦钾格列齐特 CYPC 相互作用体外预测　出处：《中国医院药学杂志》2015年12期 　论文类型：期刊论文

【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。
[Abstract]:Aim: to investigate the potential inhibition of losartan potassium on human liver microsomes or recombinant enzyme CYP2C9 and the kinetic parameters of the enzyme. The effects of losartan potassium on the area under the plasma concentration-time curve of gliclazide were evaluated by a predictive model. Methods: different concentrations of losartan potassium (over IC50) and substrate diclofenac sodium (across km) were used. Value) to determine the corresponding metabolic rate, The reversible inhibition type was determined by Dixon mapping and Lineweaver-Burk mapping, and the enzyme kinetic inhibition constant Ki. single point inactivation method was used to determine whether Losartan potassium inhibition to CYP2C9 was based on mechanism, and combined with Ki value of losartan potassium. Other body parameters and Gliclazide's FM values were used to predict the extent of drug-drug interactions in the body. Results: Dixon and Lineweaver-Burk were used to map. The results showed that the inhibition of CYP2C9 by Losartan potassium belonged to non-competitive inhibition. The inhibitory constants of potassium losartan on CYP2C9 and recombinant enzyme CYP2C9 in human liver microsomes were 16.05 and 53.02 渭 mol 路L-1, respectively. There was no opportunistic inhibition of Losartan potassium on CYP2C9. Losartan potassium can increase the AUC of combined gliclazide by 0.10% or 0.03.Conclusion: losartan potassium is not easy to cause large changes of gliclazide AUC under the usual dosage condition in clinic, but whether the two drugs can be used in combination widely. Long-term clinical trials are needed to verify this.
【作者单位】：台州市中心医院药剂科;
【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)
【分类号】：R969

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