Isolation and identification of major urinary metabolites of rifabutin in rats and humans.
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.
Utkin
I
I
Department of Pharmacology, College of Medicine, The Ohio State University, Columbus 43210, USA.
Koudriakova
T
T
Thompson
T
T
Cottrell
C
C
Iatsimirskaia
E
E
Barry
J
J
Vouros
P
P
Gerber
N
N
D000293:Adolescent; D000328:Adult; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000652:urine*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D017828:Rifabutin / Q000652:urine*; D013045:Species Specificity
D000904:Antibiotics, Antitubercular; D017828:Rifabutin