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A limited sampling strategy of phenotyping probe midazolam to predict inhibited activities of hepatic CYP3A in rats

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Author:: No author available

Journal Title:: ACTA PHARMACEUTICA SINICA

Issue:: 9

DOI:: 10.3321/j.issn:0513-4870.2008.09.005

Key Word:: 有限采样法;CYP3A;咪哒唑仑;酮康唑

Abstract：本研究以细胞色素P450(CYP)3A探针药物咪哒唑仑的系统清除率(CLs)为指标,评价有限采样法(LSS)预测肝脏CYP3A抑制状态的可行性.采用系列剂量的CYP3A选择性抑制剂酮康唑预处理大鼠,静脉注射咪哒唑仑(MDZ)后若干时间点收集血浆样品并检测MDZ浓度,经逐步回归分析和Jack-knife验证建立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.通过绘制Bland-Altman散点图对由两点(60和90 min)或三点(30、60和90 min,或30、60和120 min)血浆药物浓度建立的LSS预测模型得到的CLs估计值(CLest)与二房室模型拟合值(观察值,CLobs)进行偏差分析并计算95%可信区间,表明两种方法得到的CLs具有较好的一致性,LSS法预测误差小,特别是两点LSS预测模型更为准确且简便.结果表明:以咪哒唑仑清除率为指标,采用有限采样法评价大鼠肝脏CYP3A抑制状态下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治疗药物的给药方案提供了理论依据和实验室证据.

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