Dasatinib

At nanomolar concentrations, Dasatinib inhibits these kinases: BCR-ABL, the SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2 and PDGFRβ. Modeling studies predict that Dasatinib binds to several conformations of the ABL kinase. In vitro, it was active in leukemic cell lines representing both imatinib mesylate-sensitive and resistant disease. It slowed the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines that overexpress BCR-ABL. Under the conditions of the assays, Dasatinib could overcome Imatinib resistance caused by BCR-ABL kinase domain mutations, by activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and by overexpression of the multi-drug resistance gene.

Absorption: After oral use, the maximum plasma concentrations (Cmax) of Dasatinib are seen between 0.5 hours and 6 hours (Tmax).

Food Effect: A high-fat meal raised the mean AUC of Dasatinib by 14% after a single 100 mg dose. That meal contained 985 kcal in total. The calories came 52% from fat, 34% from carbohydrates and 14% from protein.

Distribution: The apparent volume of distribution is 2505 (CV% 93%). In vitro, about 96% of Dasatinib was bound to human plasma proteins, and about 93% of its active metabolite. This did not change with concentration over the range of 100 ng/ml to 500 ng/ml. In vitro, Dasatinib is a P-gp substrate.

Elemination: The mean terminal half-life of Dasatinib is 3 hours to 5 hours. The mean apparent oral clearance is 363.8 l/hr (CV% 81.3%).

Metabolism: Dasatinib is metabolized in humans, mainly by CYP3A4. CYP3A4 is also the main enzyme that forms the active metabolite. Flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes take part in forming Dasatinib metabolites too. The active metabolite is equipotent to Dasatinib, but its exposure is only about 5% of the AUC of Dasatinib. It is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also has several other inactive oxidative metabolites.

Excretion: Elimination is mainly through the feces. After a single radiolabeled oral dose of Dasatinib, 4% of the administered radioactivity was recovered in the urine and 85% in the feces within 10 days. Unchanged Dasatinib made up 0.1% of the administered dose in the urine and 19% in the feces. The rest of the dose was metabolites.