Abstract
This study describes the in vitro metabolism of [14C]dasatinib in liver tissue incubations from rat, monkey, and human and the in vivo metabolism in rat and monkey. Across species, dasatinib underwent in vitro oxidative metabolism to form five primary oxidative metabolites. In addition to the primary metabolites, secondary metabolites formed from combinations of the oxidative pathways and conjugated metabolites of dasatinib and its oxidative metabolites were also observed in hepatocytes incubations. In in vivo studies in rats and monkeys, the majority of the radioactive dose was excreted in the bile and feces. In bile duct–cannulated monkeys after an i.v. dose, 13.7% of the radioactive dose was excreted in the feces through direct secretion. Dasatinib comprised 56 and 26% of the area under the curve (AUC) (0–8 h) of total radioactivity (TRA) in plasma, whereas multiple metabolites accounted for the remaining 44 and 74% of the AUC (0–8 h) of TRA for rats and monkeys, respectively. In rat and monkey bile, dasatinib accounted for <12% of the excreted dose, suggesting that dasatinib was extensively metabolized before elimination. The metabolic profiles in bile were similar to the hepatocyte profiles. In both species, a large portion of the radioactivity excreted in bile (≥29% of the dose) was attributed to N-oxides and conjugated metabolites. In rat and monkey feces, only the oxidative metabolites and their further oxidation products were identified. The absence of conjugative or N-oxide metabolites in the feces suggests hydrolysis or reduction, respectively, in the gastrointestinal tract before elimination.
Footnotes
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L.J.C. and D.C. contributed equally to this work.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.018234.
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ABBREVIATIONS: dasatinib, BMS-354825, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide; CML, chronic myelogenous leukemia; LC/MS/MS, liquid chromatography/tandem mass spectrometry; BDC, bile duct-cannulated; GI, gastrointestinal; TRA, total radioactivity; HPLC, high-performance liquid chromatography; MS, mass spectrometry; PAPS, 3′-phosphoadenosine-5′-phosphosulfate; TK, toxicokinetic; AUC, area under the curve; TFA, trifluoroacetic acid; ESI, electrospray ionization; DMSO, dimethyl sulfoxide; HMBC, heteronuclear multiple-bond correlation spectroscopy.
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↵1 Current affiliation: Department of Drug Metabolism, Merck and Co., Inc., West Point, PA.
- The American Society for Pharmacology and Experimental Therapeutics
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