Abstract

3′-tert-Butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxy-paclitaxel (BMS-275183) is a taxane analog that has the potential for oral use in the treatment of various types of cancer. In this study, the metabolism and excretion of [¹⁴C]BMS-275183 were evaluated after a single oral administration of [¹⁴C]BMS-275183 to rats and dogs (15 and 1 mg/kg, respectively). To aid metabolite identification by mass spectrometry (MS), a stable labeled (phenyl-¹³C₆) BMS-275183 was included in 1:1 ratio of ¹³C₆/¹²C in the dose administration. Fecal excretion was the major route of elimination for [¹⁴C]BMS-275183 in both species (85–86 and <9% of the dose in feces and urine, respectively). The highest radioactivity in plasma was observed at 1 h postdose, suggesting rapid absorption of the drug in both species. The total radioactivity in plasma was measurable up to 24 h postdose. Metabolites were identified by liquid chromatography-MS and/or NMR spectroscopy. [¹⁴C]BMS-275183 was the prominent component in rat and dog plasma and was detected up to 24 h along with various oxidative and hydrolytic metabolites. [¹⁴C]BMS-275183 was extensively metabolized in both species, forming mainly oxidative metabolites, and unchanged parent drug accounted for <3.5% of the administered dose in urine and feces. The prominent metabolites resulted from oxidation of the tert-butyl groups on the side chain and further oxidation and cyclization of the tert-butylhydroxylated metabolites. A total of 30 oxidative metabolites including M13, a prominent ester cleavage metabolite, were identified in rat and dog samples.