Study on a Limited Sampling Strategy to Predict the Metabolic Activity of Hepatic CYP 3A with Phenotyping Probe Midazolam in Rats Developing Liver Injury Induced by Carbon Tetrachloride

ZHU Xue-hui;JIO Jin-jie;ZHNG Ci-li;LOU Jin-shi;LIU Chng-xio

Chinese Pharmaceutical Journal ›› 2009, Vol. 44 ›› Issue (23) : 1777-1781.

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Chinese Pharmaceutical Journal ›› 2009, Vol. 44 ›› Issue (23) : 1777-1781.
Article

Study on a Limited Sampling Strategy to Predict the Metabolic Activity of Hepatic CYP 3A with Phenotyping Probe Midazolam in Rats Developing Liver Injury Induced by Carbon Tetrachloride

  • ZHU Xue-hui 1a ,1b ， JIAO Jian-jie1b ， ZHANG Cai-li1b ， LOU Jian-shi1b* ， LIU Chang-xiao2
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Abstract

OBJECTIVE To evaluate the feasibility of a limited sampling strategy (LSS) for the prediction of damaged hepatic CYP3A activity by the systemic clearance of midazolam (MDZ), a CYP3A phenotyping probe. METHODS Rats pretreated with or without serial concentrations of carbon tetrachloride （CCl4） solutions were used as training set. After 24 h, the activities of serum ALT and AST were detected. Linear regression analysis and a Jack-knife validation procedure was performed based on plasma MDZ concentrations at specific times after sublingual vein injection of MDZ to establish the most informative LSS equations for accurately estimating the clearance of MDZ. Another rats in the same setting was used as the validation set to confirm the individual values of estimated clearance （CLest） that were derived from the predictive equations developed in the training set. RESULTS Series of CCl4 solutions induced different degree of liver injury. LSS models derived from single or two sampling time points, at 45 min and 5.45 min, exhibited a good accuracy and acceptable error for estimating the CLobs of MDZ to evaluate hepatic CYP3A activity, especially the 5.45 min LSS model showed more accurate. CONCLUSION The results support the hypothesis that limited sampling strategy is less complicated than the usual method for estimating hepatic CYP3A phenotyping by predicting the systemic clearance of MDZ clearance when liver is damaged in rats. The present study provided theoretical basis and laboratory evidence for LSS to clinically evaluate metabolizing function of liver and design rational drug regimen.

Key words

limited sampling strategy / cytochrome P450 3A / midazolam / liver / carbon tetrachloride

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ZHU Xue-hui;JIO Jin-jie;ZHNG Ci-li;LOU Jin-shi;LIU Chng-xio . Study on a Limited Sampling Strategy to Predict the Metabolic Activity of Hepatic CYP 3A with Phenotyping Probe Midazolam in Rats Developing Liver Injury Induced by Carbon Tetrachloride[J]. Chinese Pharmaceutical Journal, 2009, 44(23): 1777-1781

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（ 收稿日期 ： 2009-02-12 ）


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