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Metabolism and Excretion of an Oral Taxane Analog, [¹⁴C]3'-tert-Butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debenzoyl-4-O-methoxy-paclitaxel (BMS-275183), in Rats and Dogs

Van T. Ly, Janet Caceres-Cortes, Donglu Zhang, W. Griffith Humphreys, Ihoezo V. Ekhato, Donald Everett, and S. Nilgün Çömezolu

Departments of Biotransformation (V.T.L., D.Z., W.G.H., D.E., S.N.C.), Bioanalytical and Discovery Sciences (J.C.C.), and Chemical Synthesis (I.V.E.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey

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.

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				D. Zhang, V. T. Ly, M. Lago, Y. Tian, J. Gan, W. G. Humphreys, and S. N. Comezoglu CYP3A4-Mediated Ester Cleavage as the Major Metabolic Pathway of the Oral Taxane 3'-tert-Butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (BMS-275183) Drug Metab. Dispos., April 1, 2009; 37(4): 710 - 718. [Abstract] [Full Text] [PDF]