title: In vitro metabolism of FK-506 in rat, rabbit, and human liver microsomes: identification of a major metabolite and of cytochrome P450 3A as the major enzymes responsible for its metabolism.
abstract: The metabolism of the immunosuppressant FK-506 was shown to be catalyzed primarily by cytochrome P450 isozymes of the P450 3A subfamily. Antibodies against rat P450 3A inhibited FK-506 metabolism by 82% in rat liver microsomes and by 35-56% in liver microsomes from humans, dexamethasone-induced rats, and erythromycin-induced rabbits. Poor species cross-reactivity of the antibodies, metabolic switching, and/or some metabolism by P450 isozymes other than P450 3A may be responsible for the incomplete inhibition observed. Besides anti-rat P450 3A, antibodies against rat P450 1A also appeared to have some inhibitory effect implicating these particular cytochrome P450 isozymes as having a minor role in FK-506 metabolism. The formation of 13-desmethyl FK-506, identified here as a major metabolite of FK-506 in all types of microsomes examined, was inhibited completely by anti-P450 3A in liver microsomes from dexamethasone-induced rats and erythromycin-induced rabbits but only partially in human and control rat liver microsomes.
authors.affiliation: Department of Animal and Exploratory Drug Metabolism, Merck Sharp & Dohme Research Laboratories, New Jersey 07065.
authors.forename: S H
authors.initials: SH
authors.lastname: Vincent
authors.forename: B V
authors.initials: BV
authors.lastname: Karanam
authors.forename: S K
authors.initials: SK
authors.lastname: Painter
authors.forename: S H
authors.initials: SH
authors.lastname: Chiu
mesh_terms: D000328:Adult; D000818:Animals; D000906:Antibodies; D001711:Biotransformation; D002250:Carbon Radioisotopes; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011335:Proadifen / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D016559:Tacrolimus / Q000378:metabolism*; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D000906:Antibodies; D002250:Carbon Radioisotopes; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D016559:Tacrolimus