METABOLISM OF TACROLIMUS (FK-506) IN RAT-LIVER MICROSOMES EFFECT OF RIFAMPIN AND DEXAMETHASONE

The in vitro metabolism of tacrolimus (TAC, FK 506) was investigated i n the liver microsomes prepared from normal rats as well as rats treat ed with dexamethasone (DEX) and rifampin (RIF). The rate of tacrolimus metabolism was similar in control and RIF treated rat liver microsome s, whereas it significantly increased in microsomes obtained from dexa methasone treated rats. Seven different possible metabolites were iden tified in the microsomal preparations from rats treated with rifampin or dexamethasone whereas the microsomes from the control rats failed t o produce the mono-demethylated and monohydroxylated metabolite of TAC (TAC+2, m/z = 805.5). There was an apparent difference in the amount of individual metabolites formed in different groups. This indicates q uantitative differences in the induction of cytochrome P450 3A, an enz yme sub family known to be primarily responsible for tacrolimus metabo lism. Lack of induction of tacrolimus metabolism by rifampin can be at tributed to the lack of effect of rifampin in inducing cytochrome P450 3A in rats.