RT Journal Article
SR Electronic
T1 Metabolism and Excretion of an Oral Taxane Analog, [<sup>14</sup>C]3′-<em>tert</em>-Butyl-3′-<em>N-tert</em>-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-<em>N</em>-debenzoyl-4-<em>O</em>-methoxy-paclitaxel (BMS-275183), in Rats and Dogs
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1115
OP 1128
DO 10.1124/dmd.108.025809
VO 37
IS 5
A1 Van T. Ly
A1 Janet Caceres-Cortes
A1 Donglu Zhang
A1 W. Griffith Humphreys
A1 Ihoezo V. Ekhato
A1 Donald Everett
A1 S. Nilgün Çömezoğlu
YR 2009
UL http://dmd.aspetjournals.org/content/37/5/1115.abstract
AB 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 &lt;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 &lt;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. The American Society for Pharmacology and Experimental Therapeutics