Abstract
SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [14C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (Tmax ∼0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of <4 h. Dasatinib was the major drug-related component in human plasma. At 2 h, dasatinib accounted for 25% of the TRA in plasma, suggesting that metabolites contributed significantly to the total drug-related component. There were many circulating metabolites detected that included hydroxylated metabolites (M20 and M24), an N-dealkylated metabolite (M4), an N-oxide (M5), an acid metabolite (M6), glucuronide conjugates (M8a,b), and products of further metabolism of these primary metabolites. Most of the administered radioactivity was eliminated in the feces (85%). Urine recovery accounted for <4% of the dose. Dasatinib accounted for <1 and 19% of the dose in urine and feces, respectively, suggesting that dasatinib was well absorbed after p.o. administration and extensively metabolized before being eliminated from the body. The exposures of pharmacologically active metabolites M4, M5, M6, M20, and M24 in patients, along with their cell-based IC50 for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity.
Footnotes
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Part of this work has been presented previously at the 2006 International Society for the Study of Xenobiotics meeting, 2005 American Association of Pharmaceutical Scientists meeting, and 2007 American Association for Cancer Research meeting.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.018267.
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ABBREVIATIONS: dasatinib, BMS-354825, [N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)-thiazole-5-carboxamide]; CML, chronic myelogenous leukemia; ADME, absorption, distribution, metabolism, and excretion; HPLC, high-performance liquid chromatography; TRA, total radioactivity; LC/MS/MS, liquid chromatography/tandem mass spectrometry; LSC, liquid scintillation counting; IS, internal standard; GI, gastrointestinal.
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↵1 Current affiliation: Department of Drug Metabolism, Merck and Co., Inc., West Point, PA.
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↵2 Current affiliation: Genentech, South San Francisco, CA.
- Received August 12, 2007.
- Accepted April 16, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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