Abstract

Rifapentine is a cyclopentyl derivative of rifampin under development for the treatment of Mycobacterium tuberculosisand Mycobacterium avium complex infections. These studies were designed to investigate the disposition and biotransformation of single iv and oral doses of ¹⁴C-rifapentine in mice, bile duct–cannulated and uncannulated rats, and monkeys. Mass balance studies included ¹⁴C analyses of urine, feces, bile, cage wash, carcasses, and cage air collected for up to 120 hr postdose. Separation of radioactive compounds extracted from urine, bile, and feces was conducted using high-performance liquid chromatography and radioisotope detection. The mass spectra of selected chromatographic peaks were obtained. Disposition results were similar for all three species. Less than 5% of the radioactive dose of¹⁴C-rifapentine was recovered in urine, indicating that renal excretion is a minor route of elimination in these species. The major route of elimination of radioactivity was into the feces, where more than 75% of the radioactivity was recovered. Biliary excretion was the major route of elimination of radioactivity in bile duct-cannulated rats dosed either po or IV. Radiochromatograms were similar for fecal samples from animals dosed by IV or orally. Ten regions of radioactivity were observed in mouse and rat fecal sample radiochromatograms, and seven regions of radioactivity were observed in monkey fecal sample radiochromatograms. The most abundant compound identified in feces was usually intact rifapentine (27%–41% of dose in mouse, 3%–35% of dose in rat, and 17%–29% of dose in monkey). Other peaks identified or characterized in feces based on liquid chromatography/ultraviolet/¹⁴C and/or liquid chromatography/mass spectrometry methods included 25-desacetyl-rifapentine, 3-formyl-25-desacetyl-rifapentine, and 3-formyl-rifapentine. The compounds rifapentine, 25-desacetyl-rifapentine, and 3-formyl-rifapentine were present in rat bile samples. These studies show that the metabolism and disposition of rifapentine in mice, rats, and monkeys were similar.