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 significantly inhibited FK 506 metabolism. Although cyclosporine is a known substrate of cytochrome P-450 IIIA, it had 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 that 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.