Metabolism and Excretion of an Oral Taxane Analog, [ 14 C]3-tert- Butyl-3-N-tert-butyloxycarbonyl-4-deacetyl-3-dephenyl-3-N- debenzoyl-4-O-methoxy-paclitaxel (BMS-275183), in Rats and Dogs □ S Van T. Ly, Janet Caceres-Cortes, Donglu Zhang, W. Griffith Humphreys, Ihoezo V. Ekhato, Donald Everett, and S. Nilgu ¨nC ¸o ¨ mezog ˘ lu 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 Received November 24, 2008; accepted February 4, 2009 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 [ 14 C]BMS-275183 were evaluated after a single oral administration of [ 14 C]BMS-275183 to rats and dogs (15 and 1 mg/kg, respec- tively). To aid metabolite identification by mass spectrometry (MS), a stable labeled (phenyl- 13 C 6 ) BMS-275183 was included in 1:1 ratio of 13 C 6 / 12 C in the dose administration. Fecal excretion was the major route of elimination for [ 14 C]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. Me- tabolites were identified by liquid chromatography-MS and/or NMR spectroscopy. [ 14 C]BMS-275183 was the prominent compo- nent in rat and dog plasma and was detected up to 24 h along with various oxidative and hydrolytic metabolites. [ 14 C]BMS-275183 was extensively metabolized in both species, forming mainly oxi- dative 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 iden- tified in rat and dog samples. Paclitaxel, which was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia (Wani et al., 1971; Wall and Wani, 1995), belongs to a class of anticancer agents known as taxanes. Paclitaxel has been widely used with success in patients with ovarian, breast, and lung cancer and an advanced form of Kaposi’s sarcoma (Rowinsky and Donehower, 1995; Saville et.al., 1995). Docetaxel, a semisynthetic taxane analog, is also active against a wide variety of solid tumors such as ovarian, lung, breast, and head and neck cancer (Bissery et al., 1995; van Oosterom and Schrijvers, 1995; Clarke and Rivory, 1999). The mecha- nism of the taxanes involves inhibition of the microtubule function by stabilizing GDP-bound tubulin in the microtubule. Microtubules are essential to cell division, and taxanes therefore stop the cell division. Paclitaxel and docetaxel are administered to patients intravenously because of their poor oral bioavailability (Sparreboom et al., 1997). Oral treatment for the chemotherapy agents is preferred as this ad- ministration route is convenient to patients, reduces administration costs, and facilitates the use of more chronic treatment regimens. BMS-275183 is one of many taxane analogs that has a potential for oral use in the treatment of cancer (Bro ¨ker et al., 2007). This com- pound is a C-4 methyl carbonate analog of paclitaxel that contains additional modifications on the side chain where two phenyl groups were replaced by tert-butyl groups (Mastalerz et al., 2003). BMS- 275183 exhibited good oral bioavailability in animals and had anti- tumor activity that was comparable with that of intravenous paclitaxel (Rose et al., 2001; Mastalerz et al., 2003). Stable isotope-labeled drugs are widely used in many pharmacoki- netic and drug metabolism studies including as standards in bioana- lytical analysis, in determination of bioavailability, in drug metabo- lism profiling, in elucidation of drug biotransformation mechanisms, and in metabolite identification (Baillie and Rettenmeier 1986; Abramson et al., 1996; Baillie et al., 2001; Tong et al., 2006; Lim et al., 2008). The commonly used stable isotopes are 2 H, 13 C, 15 N, 18 O, Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.108.025809. □ S The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material. ABBREVIATIONS: BMS-275183, 3'-tert-butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debenzoyl-4-O-methoxy-paclitaxel; MS/ MS, tandem mass spectrometry; LC, liquid chromatography; HPLC, high-performance liquid chromatography; COSY, correlation spectroscopy; TOCSY, total correlation spectroscopy; HMQC, heteronuclear multiple quantum coherence; HMBC, heteronuclear multiple bond correlation; amu, atomic mass units; P, parent drug. 0090-9556/09/3705-1115–1128$20.00 DRUG METABOLISM AND DISPOSITION Vol. 37, No. 5 Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 25809/3460005 DMD 37:1115–1128, 2009 Printed in U.S.A. 1115 http://dmd.aspetjournals.org/content/suppl/2009/02/06/dmd.108.025809.DC1 Supplemental material to this article can be found at: at ASPET Journals on August 18, 2017 dmd.aspetjournals.org Downloaded from