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目的以细胞色素P450(CYP)3A探针药物咪哒唑仑(MDZ)的系统清除率(CLs)为指标,评价有限采样法(LSS)预测肝脏损伤状态下CYP3A代谢活性的可行性。方法采用系列浓度的四氯化碳溶液预处理大鼠,24h后,静脉注射MDZ,在若干时间点采血检测血浆MDZ浓度。留取血清并检测丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)活性。经逐步回归分析和Jack-knife方法验证,建立最终的LSS模型。对经相同处理的另一随机群体进行验证分析,评价该LSS模型方程的准确性和重现性。结果系列浓度四氯化碳溶液造成肝脏不同程度损伤。由单点(45min)或两点(5,45min)血浆药物浓度建立的LSS预测模型所得到的CLs估计值(CLest)与实际计算值(CLobs)之间具有良好的相关性,误差小。两点LSS模型对样本预测的相关性较单点LSS更优(r=0.96),而单点LSS模型则更显简便。结论本实验表明,以MDZ清除率为指标,采用45min或5.45min的有限采样方案评价肝脏损伤状态下CYP3A的代谢活性是一种准确而简便的方法,为今后推广到临床评价肝脏代谢功能从而制定和调整给药方案提供了理论依据和实验室证据。
Objective To evaluate the feasibility of LSS in predicting the metabolic activity of CYP3A in hepatic injury by using the systemic clearance rate (CLs) of cytochrome P450 (CYP) 3A probe drug MDZ. Methods Rats were pretreated with a series of concentrations of carbon tetrachloride solution. After 24 hours, MDZ was injected intravenously and plasma concentrations of MDZ were measured at several time points. Serum was collected and tested for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. After stepwise regression analysis and Jack-knife method validation, the final LSS model was established. Another randomized population with the same treatment was validated to evaluate the accuracy and reproducibility of the LSS model equation. The results of the concentration of carbon tetrachloride solution caused by varying degrees of liver damage. The LSS prediction model established by single point (45min) or two point (5,45min) plasma drug concentration has a good correlation between CLs and CLobs, with small error. The correlation between the two-point LSS model and the single-point LSS is better than the single-point LSS (r = 0.96), while the single-point LSS model is more convenient. Conclusion This experiment shows that using MDZ clearance rate as an index and evaluating the metabolic activity of CYP3A under liver injury by 45min or 5.45min finite sampling scheme is an accurate and simple method for the future promotion to the clinical evaluation of liver metabolism to formulate And adjust the drug delivery program provides a theoretical basis and laboratory evidence.