DISPOSITION AND METABOLISM OF C-14-RIFAPENTINE IN HEALTHY-VOLUNTEERS

Rifapentine is a long-acting cyclopentyl-derivative of rifampin. This study was designed to investigate the mass balance and biotransformati on of C-14-rifapentine in humans. Four healthy male volunteers receive d a single 600-mg oral dose of C-14-rifapentine in a hydroalcoholic so lution. Whole blood, urine, and fecal samples were collected before an d at frequent intervals after drug administration. Amount of radioacti vity recovered in urine and feces was assessed for up to 18 days postd ose. Metabolite characterization in urine and feces was conducted usin g high-performance liquid chromatography with radiometric detection an d liquid chromatography/mass spectroscopy. The total recovery of radio active dose was 86.8%, with the majority of the radioactive dose recov ered in feces (70.2%). Urine was a minor pathway for excretion (16.6% of the dose recovered). More than 90% of the excreted radioactivity wa s profiled as C-14 chromatographic peaks and 50% was structurally char acterized. These characterized compounds found in feces and urine were rifapentine, 25-desacetyl-rifapentine, 3-formyl-rifapentine, and 3-fo rmyl-25-desacetyl-rifapentine. The 25-desacetyl metabolite, formed by esterase enzymes found in blood, liver, and other tissues, was the mos t abundant compound in feces and urine, contributing 22% to the profil ed radioactivity in feces and 54% in urine. The 3-formyl derivatives o f rifapentine and 25-desacetyl-rifapentine, formed by nonenzymatic hyd rolysis, were also prominent in feces and, to a lesser extent, in urin e. In contrast to the feces and urine, rifapentine and 25-desacetyl-ri fapentine accounted for essentially all of the plasma radioactivity (9 9% of the C-14 area under the concentration-time curve), indicating th at 25-desacetyl-rifapentine is the primary metabolite in plasma. It ap pears, therefore, that the nonenzymatic hydrolysis of rifapentine to 3 -formyl byproducts occurs primarily in the gut and the acidic environm ent of the urine.