FK-506 (TACROLIMUS) METABOLISM BY RAT-LIVER MICROSOMES AND ITS INHIBITION BY OTHER DRUGS

The in vitro metabolism of FK 506 and its inhibition by other drugs wa s Studied with hepatic microsomes from rats pre-treated with dexametha sone, a selective cytochrome P-450 IIIA inducer. Nonspecific inhibitor s of cytochrome P-450, such as ketoconazole, itraconazole, fluconazole and SKF 525 A, and most of the cytochrome P-450 IIIA specific substra tes used in this study significatly inhibited FK 506 metabolism. Altho ugh cyclosporine is a known substrate of cytochrome P-450 IIIA, it bad no effect on FK 506 metabolism. Cytochrome P-450 II substrates had mi nimal but significant effect on FK 506 metabolism. This data supports our earlier observations hat FK 506 metabolism is mediated predominant ly by the steroid inducible cytochrome P-450 IIIA enzyme subfamily. Th e results of this study indicate that in transplant patients there is a potential for an interaction of FK 506 with other drugs that are met abolized by the cytochrome P-450 IIIA subfamily or those that alter th e activity of cytochrome P-450 IIIA subfamily. Careful monitoring and FK 506 dosing adjustment may be necessary to maintain therapeutic conc entration and minimize toxicity in patients receiving this agent.