Abstract 1528: Abcc4 (Mrp4)-deficiency leads to decreased oral absorption of dasatinib

Dasatinib, an orally available multikinase inhibitor, has been recently approved for imatinib- resistant chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. As with other tyrosine kinase inhibitors, dasatinib exhibits extensive interindividual pharmacokinetic variability, the causes of which are presently unknown. Previously, a notable degree of variability was observed with dasatinib oral absorption (time to peak concentration ranging from 0.5 to 6 h) and overall systemic exposure (CV, ∼50%) in patients (Demetri et al, Clin Cancer Res 2009). Identifying the factors underlying this variability may help enable clinicians to better manage the balance between dasatinib efficacy and toxicity. Here, we evaluated the role of ABCC4 (MRP4), a member of the ATP-binding cassette transporter family, as a factor regulating the oral absorption of dasatinib. Results from ABCC4-overexpressing inside-out vesicles indicated that dasatinib, at clinically relevant concentrations, was actively transported by ABCC4. Saturation of ABCC4-related transport was not seen even at a dasatinib concentration of 65 µM, suggesting high capacity transport. Dasatinib (1 µM) accumulation was increased ∼3-fold after a 5-min incubation in ABCC4-overexpressing vesicles compared to empty vector controls. The encouraging in vitro results prompted us to assess the in vivo role of ABCC4 in dasatinib absorption using Abcc4 knockout mice on a C57BL/6 background (Abcc4(-/-) mice) (Leggas et al, Mol Cell Biol 2004). Oral administration of dasatinib (10 mg/kg, in 50 mM sodium acetate buffer pH 4.6) to both wildtype mice and Abcc4(-/-) mice resulted in significant differences (P = 0.015) in dasatinib plasma concentrations at 4 out of 6 samples collected at serial time points. The largest difference was observed at 15 min, where dasatinib plasma concentrations in the Abcc4(-/-) mice were 5-fold decreased compared with wildtype mice. Although later time points also showed a decrease in dasatinib concentrations in Abcc4(-/-) mice (3.2-fold at 30 min; 2.2-fold at 1 h; 1.5-fold at 2 h), there was a convergence of the plasma curves by 4 h, suggesting that absorption rather than elimination pathways of dasatinib were altered in the Abcc4(-/-) mice. Indeed, pharmacokinetic analyses revealed a nearly 12-fold (P = 0.014) decrease in the dasatinib absorption rate constant in Abcc4(-/-) mice compared with wildtype mice, whereas the terminal half-life was unchanged (P = 0.41). The reduced absorption of dasatinib in Abcc4(-/-) mice was associated with a 4-fold (P = 0.019) decrease in peak concentration and a 2-fold decrease in AUC (P = 0.041). Collectively, these findings demonstrate that ABCC4 plays an important role in the intestinal absorption of dasatinib and reveal a new host factor that may contribute to enhanced interindividual pharmacokinetic variability in patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1528.