Metabolism and Disposition of Dasatinib after Oral Administration to Humans

Abstract

SPRYCEL (dasatinib; Bristol-Myers Squibb, Princeton, NJ) is a multiple kinase inhibitor that potently inhibits Bcr-Abl, Src family (Src, Lck, Yes, Fyn), c-Kit, EPHA2, and platelet-derived growth factor receptor ␤ kinases (Lombardo et al., 2004;Shah et al., 2004;Das et al., 2006). It is currently approved in the United States and European Union to treat chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec, Novartis, Basel, Switzerland). Unlike imatinib mesylate, which binds to the closed confirmation of Bcr-Abl kinase, dasatinib was designed to bind to both the open and closed form of the enzyme (Shah et al., 2004;Tokarski et al., 2006). Because of this binding property and the ability to inhibit multiple kinases, including Src, dasatinib is effective in tumors that are resistant to imatinib mesylate (O'Hare et al., 2005;Schittenhelm et al., 2006). Clinical studies have shown that dasatinib shows clinical response in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to imatinib mesylate treatment Hochhaus et al., 2006;Talpaz et al., 2006;Quintas-Cardama et al., 2007).Numerous in vitro and in vivo studies have been conducted with dasatinib in nonclinical species to understand its absorption, distribution, metabolism, and excretion (ADME) properties and gauge the suitability of these species as toxicological models Kamath et al., 2008). The metabolic profiles from in vitro studies in liver microsomes, and hepatocytes showed good correlation with the in vivo profiles generated after a single p.o. dose of [14 C]dasatinib to rats and monkeys. The primary metabolites of dasatinib Article, publication date, and citation information can be found at

Metabolism of Fostamatinib, the Oral Methylene Phosphate Prodrug of the Spleen Tyrosine Kinase Inhibitor R406 in Humans: Contribution of Hepatic and Gut Bacterial Processes to the Overall Biotransformation

“…These results indicate that gut bacteria are capable of modifying hepatic-derived drug metabolites by pathways other than the commonly recognized reductive (Zachariah and Juchau, 1974) and hydrolytic pathways (Christopher et al, 2008).…”

Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up

“…After administration, dasatinib is extensively metabolized, with an elimination half-life of less than 4 hours. 26 In a study of patients enrolled in a phase 1 trial, levels of phosphorylated CrkL, a marker for Bcr-Abl activity, decreased in a dose-dependent manner 4 hours after an initial dose of dasatinib. 27 As dasatinib serum levels declined, CrkL phosphorylation was restored, indicating that once-daily dosing resulted in transient Bcr-Abl inhibition.…”

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

“…These values were estimated from results of a human ADME study with [ 14 C]dasatinib (Christopher et al, 2008b) and current study. For inhibition by ketoconazole,…”

“…14 C]dasatinib, the fraction clearance to form M4 (2.7%), M5 (1.4%), M6 (9.0%), M20 (31.4%), M24 (4.2%), and related secondary metabolites represented approximately 81% of total dasatinib clearance (Christopher et al, 2008b).…”