Abstract
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, wasN-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 theN-isobutyl-piperidyl group of rifabutin were found in the urine of rats, but not humans.
Footnotes
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Send reprint requests to: Dr. Ilya Utkin, Department of Pharmacology, The Ohio State University, 333 West 10th Avenue, 5084 Graves Hall, Columbus, OH 43210.
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Fourier transform-NMR spectra at 500 and 600 MHz were obtained at The Ohio State University Campus Chemical Instrument Center by Dr. C. E. Cottrell, using equipment funded by the National Institutes of Health Grants 1-S10-RR01458-01A1 and RR08299, and by the National Science Foundation Grant BIR-9921639. Mass spectra were obtained at the laboratory of Paul Vouros (Northeastern University) supported by the National Institutes of Health Grant IROICA 69390-01.
- Abbreviations used are::
- po
- oral
- iv
- intravenous
- MRFA
- L-methionyl-arginyl-phenylalanyl-alanine
- TEA
- triethylamine
- RT
- retention time
- ESI-MS
- electrospray ionization-mass spectrometry
- CID-MS
- collision-induced dissociation-mass spectrometry
- COSY
- correlated spectroscopy
- HMQC
- heteronuclear correlation through multiple quantum coherence
- Received December 4, 1996.
- Accepted April 24, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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