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 was Studied with hepatic microsomes from rats pre-treated with dexamethasone, a selective cytochrome P-450 IIIA inducer. Nonspecific inhibitors of cytochrome P-450, such as ketoconazole, itraconazole, fluconazole and SKF 525 A, and most of the cytochrome P-450 IIIA specific substrates used in this study significatly inhibited FK 506 metabolism. Although cyclosporine is a known substrate of cytochrome P-450 IIIA, it bad no effect on FK 506 metabolism. Cytochrome P-450 II substrates had minimal but significant effect on FK 506 metabolism. This data supports our earlier observations hat FK 506 metabolism is mediated predominantly by the steroid inducible cytochrome P-450 IIIA enzyme subfamily. The results of this study indicate that in transplant patients there is a potential for an interaction of FK 506 with other drugs that are metabolized by the cytochrome P-450 IIIA subfamily or those that alter the activity of cytochrome P-450 IIIA subfamily. Careful monitoring and FK 506 dosing adjustment may be necessary to maintain therapeutic concentration and minimize toxicity in patients receiving this agent.