ISOLATION AND IDENTIFICATION OF MAJOR URINARY METABOLITES OF RIFABUTIN IN RATS AND HUMANS

The antimycobacterial drug rifabutin is extensively metabolized in hum ans and laboratory animals. About 40% of the dose is excreted in urine as unchanged drug, and lipophilic (extractable with 1-chlorobutane) a nd polar metabolites, Polar metabolites accounted for 59.1 +/- 2.5% an d 88.8 +/- 4.4% of radioactivity in urine collected over 96 hr after i ntravenous administration of 25 and 1 mg/kg of [C-14]rifabutin to Spra gue-Dawley rats, respectively, After 48 hr, all urinary radioactivity consisted of polar metabolites, The most abundant polar metabolite, id entified by electrospray ionization-MS, collision-induced dissociation -MS, and comparison of HPLC retention times with the synthetic standar d, was N-isobutyl-4-hydroxy-piperidine, Lipophilic metabolites account ed for < 20% of urinary radioactivity, Major lipophilic metabolites, 2 5-O-deacetyl-rifabutin, 27-O-demethyl-rifabutin, 31-hydroxy-rifabutin, 32-hydroxy-rifabutin, and 20-hydroxy-rifabutin were isolated from bot h human and rat urine by HPLC and identified by electrospray ionizatio n-MS, collision-induced dissociation-MS, and NMR spectrometry, In addi tion, two metabolites formed by the oxidation of the N-isobutylpiperid yl group of rifabutin were found in the urine of rats, but not humans.