Metabolism of FK 506 in differentially induced rat liver microsomes.

The in vitro hepatic metabolism of FK 506 was studied in microsomes prepared from control rats as well as in microsomes prepared from rats treated with the selective cytochrome P-450 isozyme inducers 3-methylcholanthrene (IA), phenobarbital (IIB), and dexamethasone (IIIA). The metabolism of FK 506 was similar for control microsomes and for microsomes prepared from phenobarbital and 3-methylcholanthrene induced animals. The percentage of FK 506 metabolized by these tissue preparations ranged from 21.7 to 32.7%. In contrast, the percentage of FK 506 metabolized by dexamethasone induced microsomes was 86.4%. The metabolism of FK 506 was not effected when the selective IA and IIB isozyme inhibitors alpha-naphthoflavone and orphenadrine were added to the incubations. However, the metabolism of FK 506 decreased by approximately 44% when the IIIA specific isozyme inhibitor troleandomycin was added to the dexamethasone induced microsomes. Therefore, the metabolism of FK 506 is apparently mediated primarily by the steroid inducible cytochrome P-450 IIIA isozyme.