| Objective: To evaluate the effects of IR and IPC on the metabolic activities ofCYPIA2, CYP2C9, CYP2E1, CYP2D6 and CYP3A in rat and to estimate the activityof CYP450 with the five-drug cocktail approach.Methods: "Cocktail" approach was used to evaluate the influence of IR and IPCon the activities of CYP1A2, CYP2C9, CYP2E1, CYP2D6 and CYP3A4, whichwere reflected by the changes of pharmacokinetic parameters of 5 specific probedrugs caffeine, chlorzoxazone, tolbutamide, metoprolol and midazolam respectively.Rats were randomly divided to IR, IPC and control groups, and then injected themixture of 5 probe drugs through vena caudalis. Soon after the blood samples wereobtained through inferior caval vein at a series of time-points, the concentrations ofprobe drugs in plasma were measured by a HPLC method with UV detection. Theeffects of test drugs on the activities of CYP450 were judged indirectly by comparingthe pharmacokinetic parameters of test group with those of control group.Results: 1. The parameters including T1/2β, CLs, AUC, MRT and K10 forelimination phase exhibited similar tendency for both IR and IPC groups. Forcomparing the pharmacokinetic parameters of IR group with control group,①CLs offive probe drugs in IR group were significantly lower than those in control group(P＜0.05),and there were statistically significant differences in CLs of chlorzoxazone,tolbutamide, metoprolol and mldazolam (P＜0.01).②AUC were increased and therewere statistically significant differences in IR group (P＜0.01).③T1/2β ofchlorzoxazone, metoprolol and midazolam were prolonged in IR group (P＜0.01 orP＜0.05).④K10 of chlorzoxazone, tolbutamide, metoprolol and midazolam decreasedin IR group (P＜0.01 or P＜0.05).Comparing the pharmacokinetic parameters of IRgroup with IPC group,①CLs of five probe drugs were decreased in IR group(P＜0.05), and there were statistically significant difference in chiorzoxazone andtolbutamide (P＜0.01).②AUC of five probe drugs were increased in IR group, andthere were statistically significant difference in chlorzoxazone and tolbutamide(P＜0.01).③T1/2β of five probe drugs were prolonged but there were no significance between IR and IPC group.④K10 decreased. Moreover, statistic significance existedin chlorzoxazone and tolbutamide. 2. There were significant negative correlationbetween ALT and CLs in five probe drugs (R=-0.945～-0.552, P＜0.01, tolbutamideP＜0.05).Conclusion: 1.It suggested that the pharmacokinetic parameters derived from afive-drug cocktail approach should be a valid indicator for evaluatingdrug-metabolizing function of hepatic CYP after hepatic ischemia-reperfusion injuryand hepatic ischemic preconditioning. 2. IR could decrease the activity of cytochromeP450 in rats, and this decrease was attenuated by IPC.3.ALT could indicate thedrug-metabolizing function after liver injury roughly and indirectly.
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