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Drug Metabolism and Disposition Fast Forward
First published on April 17, 2008; DOI: 10.1124/dmd.107.018234
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Received for publication August 13, 2007.
Revised April 15, 2008.
Accepted for publication April 16, 2008.

BIOTRANSFORMATION OF [14C]DASATINIB: IN VITRO STUDIES IN RAT, MONKEY AND HUMAN AND DISPOSITION AFTER ADMINISTRATION TO RATS AND MONKEYS

Lisa J. Christopher 1, Donghui Cui 2, Wenying Li 2, Anthony Barros Jr. 2, Vinod K. Arora 2, Haiying Zhang 2, Lifei Wang 2, Donglu Zhang 2, James A Manning 2, Kan He 2, Anthony M. Fletcher 2, Marc Ogan 2, Michael Lago 2, Samuel J. Bonacorsi 2, W. Griffith Humphreys 2, Ramaswamy Iyer 2*

1 Bristol-Myers Squibb 2 Bristol-Myers Squibb Co.

* Address correspondence to: E-mail: ramaswamy.iyer{at}bms.com

Abstract

This study describes the in vitro metabolism of [14C]dasatinib in liver tissue incubations from rat, monkey and human and the in vivo metabolism in rat and monkey. Across species, dasatinib underwent in vitro oxidative metabolism to form five primary oxidative metabolites. In addition to the primary metabolites, secondary metabolites formed from combinations of the oxidative pathways as well as conjugated metabolites of dasatinib and its oxidative metabolites were also observed in hepatocytes incubations. In in vivo studies in rats and monkeys, the majority of the radioactive dose was excreted in the bile and feces. In bile-duct cannulated (BDC) monkeys after an IV dose, 13.7% of the radioactive dose was excreted in the feces through direct secretion. Dasatinib comprised of 56% and 26% of the AUC (0-8 h) of total radioactivity (TRA) in plasma, while multiple metabolites accounted for the remaining 44% and 74% of the AUC (0-8 h) of TRA for rats and monkeys, respectively. In rat and monkey bile, dasatinib accounted for <12% of the excreted dose, suggesting that dasatinib was extensively metabolized prior to elimination. The metabolic profiles in bile were similar to the hepatocyte profiles. In both species, a large portion of the radioactivity excreted in bile (≥29% of the dose) was attributed to N-oxides and conjugated metabolites. In rat and monkey feces, only the oxidative metabolites and their further oxidation products were identified. The absence of conjugative or N-oxide metabolites in the feces suggest hydrolysis or reduction, respectively, in the gastrointestinal tract prior to elimination.


Key words: anticancer agents, cytochrome P450 catalyzed oxidations, drug analysis, drug development, liver microsomes, mass spectrometry, metabolite identification, structure elucidation




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