RT Journal Article
SR Electronic
T1 Metabolism and Disposition of Dasatinib after Oral Administration to Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1357
OP 1364
DO 10.1124/dmd.107.018267
VO 36
IS 7
A1 Lisa J. Christopher
A1 Donghui Cui
A1 Chiyuan Wu
A1 Roger Luo
A1 James A. Manning
A1 Samuel J. Bonacorsi
A1 Michael Lago
A1 Alban Allentoff
A1 Francis Y. F. Lee
A1 Betty McCann
A1 Susan Galbraith
A1 Donald P. Reitberg
A1 Kan He
A1 Anthony Barros, Jr.
A1 Anne Blackwood-Chirchir
A1 W. Griffith Humphreys
A1 Ramaswamy A. Iyer
YR 2008
UL http://dmd.aspetjournals.org/content/36/7/1357.abstract
AB 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