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Received for publication August 13, 2007.
Revised April 15, 2008.
Accepted for publication April 16, 2008.
SPRYCEL® (Dasatinib, BMS-354825), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous luekemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) tumors in patients that are resistant or intolerant to imatinib mesylate (Gleevec®). After a 100 mg single oral dose of [14C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (Tmax 
0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations declined 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 oral administration and extensively metabolized prior to 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 towards in vivo activity.
Key words:
anticancer agents, cytochrome P450 catalyzed oxidations, drug clearance, drug development, drug disposition, human pharmacokinetics, mass spectrometry, metabolite identification, metabolite kinetics, pharmacokinetics
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