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Biotransformation of [¹⁴C]Dasatinib: In Vitro Studies in Rat, Monkey, and Human and Disposition after Administration to Rats and Monkeys

Departments of Pharmaceutical Candidate Optimization (L.J.C., D.C., W.L., A.B., V.K.A., H.Z., L.W., D.Z., J.A.M., K.H., W.G.H., R.A.I.), Drug Safety Evaluation (A.M.F.), and Chemical Synthesis (M.O., M.L., S.J.B.), Bristol-Myers Pharmaceutical Research and Development, Princeton, New Jersey

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.

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