Contribution of Abcc4-Mediated Gastric Transport to the Absorption and Efficacy of Dasatinib

Abstract

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 wildtype and Abcc4-null mice. The influence of Abcc4-deficiency on dasatinib efficacy was evaluated in a model of Ph+ acute lymphoblastic leukemia (ALL) by injection of luciferase-positive, p185(BCR-ABL)-expressing Arf(−/−) pre-B cells. Results Dasatinib accumulation was significantly changed in cells over-expressing ABCC4 or Abcc4 compared to control cells (P<0.001). Deficiency of Abcc4 in vivo was associated with a 1.75-fold decrease in systemic exposure to oral dasatinib, but had no influence on the pharmacokinetics of i.v. dasatinib. Abcc4 was found to be highly expressed in the stomach, and dasatinib efflux from isolated mouse stomachs ex vivo was 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 to wildtype mice (P=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.

Inhibiting Tyrosine Phosphorylation of Protein Kinase Cδ (PKCδ) Protects the Salivary Gland from Radiation Damage

“…We show that pretreatment with dasatinib, which inhibits SFKs and c-Abl, is sufficient to suppress activation and nuclear translocation of PKC␦. Further, a 20-mg/kg dose in our mouse model equates to a serum concentration that is easily obtained in patient populations (44,45). Expectedly, pretreatment with the c-Abl-selective inhibitor imatinib also blocked nuclear translocation, as evidenced by reduced binding of importin-␣ to PKC␦ following H 2 O 2 treatment.…”

ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy

“…In addition, ABCG2 and ABCC4 have some similar substrates (44). Among the ABCC4 substrates tested in the tumorspheres were an antifolate (methotrexate), (19) KI (dasatinib) (45), and camptothecin (topotecan). Topotecan is readily transported by human and murine ABCC4 (19), thus, it is conceivable that a dual inhibitor, producing combined inhibition of both ABCC4 and ABCG2, might yield greater overall improvements in survival.…”

Differential effects of thiopurine methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on mercaptopurine toxicity

“…For example, previous studies have shown that the Mrp4 substrate, dasatinib, exhibits poor oral absorption in the absence of Mrp4, due to its high expression in the stomach. [28] We postulate that decreased mercaptopurine absorption from the stomach of Mrp4 knockout mice could account for relatively greater tolerance in Mrp4 KO mice compared to TPMT KO mice.…”