Effects Of Cyclosporin A And Coadministration With Other Agents On Liver Microsomal Cytochrome P450 3A In Rats And Human

Objectives : To study the effects of cyclosporin A(CsA) and coadministration of fluconazole(Flu),methylprednisolone(MP) on the activities of rat and human cytochrome P450 3A(CYP3A).Methods: Liver microsome was preparated from normal rat and human liver,which was subjucted to be treated with a series of concentrations of CsA or coadministration with Flu or MP.The activities of CYP3A in the microsomes were detected by using erythromycin as substrate. Serum CsA concentrations of five liver transplantation recipients ,who were combined treatment CsA with MP.Results: The activities of CYP3A decreased significantly in the groups of CsA10umol/l, 20umol/l and 40umol/l,compared with control in human liver microsome.The activities decreased significantly in the group of CsA10umol/l, 20umol/l and 40umol/l vs control in rat.In all groups, the inhibition of activities were dose-dependent.In combined treatment CsA and Flu or MP,the inhibition of activities of human CYP3A were more than CsA only. Serum CsA concentrations of the recipients combined treatment CsA with MP significantly higher than that of the recipients administrating CsA only.Discussion: The studies indicate CsA is a kind of inhibitor of theCYP3A. Methylprednisolone can increase CsA bioactivities and the maximum effect occurs on day 8 after starting methylprednisolone. Flu may increase CsA bioactivities.