Metabolism and Disposition of Dasatinib after Oral Administration to Humans
Authors:
- Donghui CuiDCDonghui Cui
- Chiyuan WuCWChiyuan Wu
- Roger LuoRLRoger Luo
- James A. ManningJMJames A. Manning
- Samuel J. BonacorsiSBSamuel J. Bonacorsi
- Michael LagoMLMichael Lago
- Alban AllentoffAAAlban Allentoff
- Francis Y. F. LeeFLFrancis Y. F. Lee
- Betty McCannBMBetty McCann
- Susan GalbraithSGSusan Galbraith
- Donald P. ReitbergDRDonald P. Reitberg
- 1 July 2008
- journal article
- Published by Elsevier in Drug Metabolism and Disposition
- Vol. 36 (7) , 1357-1364
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 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 50 for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity.Keywords
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