Cancer Therapy: Preclinical Contribution of Abcc4-Mediated Gastric Transport to the Absorption and Efficacy of Dasatinib

Purpose: Several oral multikinase inhibitors are known to interact in vitro with the human ATP-binding cassette transporter ABCC4 (MRP4), but the in vivo relevance of this interaction remains poorly understood. We hypothesized that host ABCC4 activity may influence the pharmacokinetic profile of dasatinib and subsequently affect its antitumor properties. Experimental Design: Transport of dasatinib was studied in cells transfected with human ABCC4 or the ortholog mouse transporter, Abcc4. Pharmacokinetic studies were done in wild-type and Abcc4-null mice. The influence of Abcc4 deficiency on dasatinib efficacywas evaluated in amodel of Phþ acute lymphoblastic leukemia by injection of luciferase-positive, p185(BCR-ABL)-expressing Arf( / ) pre-B cells. Results: Dasatinib accumulation was significantly changed in cells overexpressing ABCC4 or Abcc4 comparedwith control cells (P < 0.001). Deficiency of Abcc4 in vivowas associatedwith a 1.75-fold decrease in systemic exposure to oral dasatinib, but had no influence on the pharmacokinetics of intravenous dasatinib. Abcc4was found to be highly expressed in the stomach, and dasatinib efflux from isolatedmouse stomachs ex vivowas impaired by Abcc4 deficiency (P < 0.01), without any detectable changes in gastric pH. Abcc4-null mice receiving dasatinib had an increase in leukemic burden, based on bioluminescence imaging, and decreased overall survival compared with wild-type mice (P 1⁄4 0.048). Conclusions: This study suggests that Abcc4 in the stomach facilitates the oral absorption of dasatinib, and it possibly plays a similar role for other orally administered substrates, such as acetylsalicylic acid. This phenomenon also provides a mechanistic explanation for the malabsorption of certain drugs following gastric resection. Clin Cancer Res; 19(16); 4359–70. 2013 AACR.