Metabolism of Tacrolimus (FK506) and its Metabolite by Rat Liver Microsomes

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The oxidative metabolism of tacrolimus (FK506) and its in vitro major metabolite was studied using rat liver microsomes. The microsomes were incubated with ¹⁴C-labeled (¹⁴C-) substrates and NADPH under aerobic condition, and the reaction products were analyzed by high-performance liquid chromatography. The 13-O-mono-demethylated metabolite (M-I) was detected as the major metabolite of 14-CFK506 at the early stage of incubation and many polar metabolites including di-demethylated and unidentified metabolites were detected at the late stage. The 13, 15 and 13, 31-O-di-demethylated metabolites (M-VII and M-VI, respectively) and more polar metabolites were produced from ¹⁴C-M-I. The oxidative metabolism of M-I by rat liver microsomes was higher in adult males than in females, was inhibited by the addition of polyclonal antibody against cytochrome P450 3A2, and was induced by the pretreatment of rats with phenobarbital and dexamethasone. These results indicate that FK506 is metabolized to polar metabolites via M-I, and the metabolism of M-I is catalyzed by rat cytochrome P450 3A subfamily, the same as in the case of FK506 metabolism.