title: FK 506 (Tacrolimus) metabolism by rat liver microsomes and its inhibition by other drugs.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, PA 15261.
authors.forename: T N
authors.initials: TN
authors.lastname: Prasad
authors.forename: D D
authors.initials: DD
authors.lastname: Stiff
authors.forename: N
authors.initials: N
authors.lastname: Subbotina
authors.forename: M A
authors.initials: MA
authors.lastname: Zemaitis
authors.forename: G J
authors.initials: GJ
authors.lastname: Burckart
authors.forename: T E
authors.initials: TE
authors.lastname: Starzl
authors.forename: R
authors.initials: R
authors.lastname: Venkataramanan
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003907:Dexamethasone / Q000494:pharmacology*; D004347:Drug Interactions; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D016559:Tacrolimus / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D002316:Cardiotonic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D003907:Dexamethasone; D016559:Tacrolimus