Dasatinib

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, Dasatinib is predicted to bind to multiple conformations of the ABL kinase. In vitro, Dasatinib was active in leukemic cell lines representing variants of imatinib mesylate-sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, Dasatinib could overcome Imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.Absorption: The maximum plasma concentrations (Cmax) of Dasatinib are observed between 0.5 hours and 6 hours (Tmax) following oral administration. Food Effect: A high-fat meal increased the mean AUC of Dasatinib following a single dose of 100 mg by 14%. The total calorie content of the high-fat meal was 985 kcal. The calories derived from fat, carbohydrates, and protein were 52%, 34%, and 14% for the high-fat meal.Distribution: The apparent volume of distribution is 2505 (CV% 93%). Binding of Dasatinib to human plasma proteins in vitro was approximately 96% and of its active metabolite was 93%, with no concentration dependence over the range of 100 ng/ml to 500 ng/ml. Dasatinib is a P-gp substrate in vitro.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, primarily by CYP3A4. CYP3A4 is the primary enzyme responsible for the formation of the active metabolite. Flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of Dasatinib metabolites. The exposure of the active metabolite, which is equipotent to Dasatinib, represents approximately 5% of the AUC of Dasatinib. The active metabolite of Dasatinib 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 primarily via the feces. Following a single radiolabeled dose of oral Dasatinib, 4% of the administered radioactivity was recovered in the urine and 85% in the feces within 10 days. Unchanged Dasatinib accounted for 0.1% of the administered dose in the urine and 19% of the administered dose in the feces with the remainder of the dose being metabolites.