IN-VIVO DISPOSITION AND METABOLISM BY LIVER AND ENTEROCYTE MICROSOMESOF THE ANTITUBERCULAR DRUG RIFABUTIN IN RATS

The in vivo disposition and in vitro metabolism of rifabutin, a new sp iropiperidylrifamycin, were studied in rats and in microsomes from rat liver and enterocytes, respectively. After i.v. doses of 1, 5, 10 and 25 mg/kg the systemic clearance was 0.7 to 1.0 liters/hr/kg; the volu me of distribution was 4.4 liters/kg for the 1 mg/kg dose and 7.4 to 7 .7 liters/kg for the 5 to 25 mg/kg doses, and the half-life ranged fro m 4.4 to 9.1 hr. Urinary and fecal excretion over 0 to 96 hr after i.v . administration of 25 mg/kg [C-14]rifabutin accounted for 40.1 and 52 .2% of the dose, respectively. Exteriorization of the bile duct showed that approximately 24% of the dose was eliminated in bile, greater th an or equal to 98% as metabolites. Bioavailability after oral administ ration of 25 and 1 mg/kg rifabutin was >90% and 44%, respectively, sug gesting significant first-pass metabolism of the lower dose. Concentra tions of rifabutin in gastric juice were 10 to 17 times higher than in blood, indicating extensive secretion into the stomach. Experiments w ith the isolated small intestinal loop demonstrated direct exsorption of the drug into the lumen. The rate of rifabutin metabolism by entero cyte microsomes was >10 times higher than that by liver microsomes, i. e., 84 and 8 pmol/min/mg protein, respectively. Biotransformation of r ifabutin in vivo and in vitro was markedly induced by dexamethasone an d inhibited by erythromycin, suggesting that CYP3A is involved in the metabolism of rifabutin. Several metabolites, including 20-OH-rifabuti n and 27-O-demethyl-rifabutin, isolated from urine and microsomes were identified by mass spectrometry and nuclear magnetic resonance spectr oscopy.