TY - JOUR T1 - Metabolism and Disposition of Dasatinib after Oral Administration to Humans JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1357 LP - 1364 DO - 10.1124/dmd.107.018267 VL - 36 IS - 7 AU - Lisa J. Christopher AU - Donghui Cui AU - Chiyuan Wu AU - Roger Luo AU - James A. Manning AU - Samuel J. Bonacorsi AU - Michael Lago AU - Alban Allentoff AU - Francis Y. F. Lee AU - Betty McCann AU - Susan Galbraith AU - Donald P. Reitberg AU - Kan He AU - Anthony Barros, Jr. AU - Anne Blackwood-Chirchir AU - W. Griffith Humphreys AU - Ramaswamy A. Iyer Y1 - 2008/07/01 UR - http://dmd.aspetjournals.org/content/36/7/1357.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -