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

Abstract

ABSTRACT:This study describes the in vitro metabolism of [ 14 C]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.

Metabolism and Disposition of [14C]BMS-690514 after Oral Administration to Rats, Rabbits, and Dogs

“…4; Table 3). The difference in the bile and fecal profiles was attributed to hydrolysis of the conjugative metabolites in the gastrointestinal tract before excretion in the feces (Parker et al, 1980;Christopher et al, 2008). M6, which was FIG.…”

“…It has been known that glucuronides typically undergo hydrolysis in the gastrointestinal tract by gut flora before excretion in the feces (Parker et al, 1980;Christopher et al, 2008). Therefore, the current studies included administration of […”

Lacteal Secretion, Fetal and Maternal Tissue Distribution of Dasatinib in Rats

“…An additional 14% of the dose was recovered in feces, suggesting direct intestinal secretion of drug-derived radioactivity (Christopher et al, 2008a).…”

Identification of the Human Enzymes Involved in the Oxidative Metabolism of Dasatinib: An Effective Approach for Determining Metabolite Formation Kinetics

“…Studies have shown that dasatinib was extensively metabolized in animals and humans (Christopher et al, 2008a,b). The primary pathways of metabolism included N-dealkylation (M4), N-oxidation (M5), carboxylic acid formation (M6), and hydroxylation (M20 and M24) (Christopher et al, 2008a). Based on the human absorption, distribution, metabolism, and excretion (ADME) study with […”