0090-9556/97/2508-0963-0969$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 8

Isolation and Identification of Major Urinary Metabolites of Rifabutin in Rats and Humans

Ilya Utkin, Tatiana Koudriakova, Toni Thompson, Charles Cottrell, Eugenia Iatsimirskaia, John Barry, Paul Vouros, and Nicholas Gerber

Department of Pharmacology, College of Medicine (I.U., T.K., E.I., N.G.) and Campus Chemical Instrument Center (C.C.), The Ohio State University; and Department of Chemistry (T.T., J.B., P.V.), Northeastern University

The antimycobacterial drug rifabutin is extensively metabolized in humans and laboratory animals. About 40% of the dose is excreted in urine as unchanged drug, and lipophilic (extractable with 1-chlorobutane) and polar metabolites. Polar metabolites accounted for 59.1 ± 2.5% and 88.8 ± 4.4% of radioactivity in urine collected over 96 hr after intravenous administration of 25 and 1 mg/kg of [¹⁴C]rifabutin to Sprague-Dawley rats, respectively. After 48 hr, all urinary radioactivity consisted of polar metabolites. The most abundant polar metabolite, identified by electrospray ionization-MS, collision-induced dissociation-MS, and comparison of HPLC retention times with the synthetic standard, was N-isobutyl-4-hydroxy-piperidine. Lipophilic metabolites accounted for <20% of urinary radioactivity. Major lipophilic metabolites, 25-O-deacetyl-rifabutin, 27-O-demethyl-rifabutin, 31-hydroxy-rifabutin, 32-hydroxy-rifabutin, and 20-hydroxy-rifabutin were isolated from both human and rat urine by HPLC and identified by electrospray ionization-MS, collision-induced dissociation-MS, and NMR spectrometry. In addition, two metabolites formed by the oxidation of the N-isobutyl-piperidyl group of rifabutin were found in the urine of rats, but not humans.