title: Metabolism and disposition of dasatinib after oral administration to humans.
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 [(14)C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (T(max) approximately 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 IC(50) for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity.
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08540, USA.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Christopher
authors.forename: Donghui
authors.initials: D
authors.lastname: Cui
authors.forename: Chiyuan
authors.initials: C
authors.lastname: Wu
authors.forename: Roger
authors.initials: R
authors.lastname: Luo
authors.forename: James A
authors.initials: JA
authors.lastname: Manning
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Bonacorsi
authors.forename: Michael
authors.initials: M
authors.lastname: Lago
authors.forename: Alban
authors.initials: A
authors.lastname: Allentoff
authors.forename: Francis Y F
authors.initials: FY
authors.lastname: Lee
authors.forename: Betty
authors.initials: B
authors.lastname: McCann
authors.forename: Susan
authors.initials: S
authors.lastname: Galbraith
authors.forename: Donald P
authors.initials: DP
authors.lastname: Reitberg
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Anthony
authors.initials: A
authors.lastname: Barros
authors.forename: Anne
authors.initials: A
authors.lastname: Blackwood-Chirchir
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.forename: Ramaswamy A
authors.initials: RA
authors.lastname: Iyer
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000069439:Dasatinib; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib