Abstract 883: Imatinib-induced modulation of gastrointestinal and hepatic membrane transporters in mice.

Abstract

Abstract Drug-induced changes in the expression or activity of ADME genes may critically affect the pharmacokinetics (PK) and the efficacy of chemotherapy as well as the incidence and severity of unwanted side effects. Drug uptake and efflux transporters are likely to be involved in the intestinal absorption, distribution and hepatic excretion of imatinib, an oral tyrosine kinase inhibitor approved for the treatment of CML and GIST. Previously, we demonstrated that imatinib is a substrate drug of both ABCB1 and ABCG2. Furthermore, we showed that prolonged imatinib exposure in Caco-2 cell cultures leads to increased expression of these drug efflux transporters. Evidently, some GIST patients chronically treated with imatinib show a time-dependent decrease in imatinib plasma levels. Altered transporter activity in the intestine and/or liver affecting the PK of imatinib may (partially) account for the observed PK resistance. We hypothesized that acquired PK resistance by decreased absorption and/or increased clearance of imatinib may be attributable to induction of intestinal and hepatic transport proteins. So, we investigated in mice whether imatinib-induced modulation of drug transporters occurs over time upon prolonged daily use of imatinib. To mimic the clinical situation we chronically treated C57/Bl6 mice, either with imatinib or with a solute control (H2O) for 4, 8 or 12 weeks. Imatinib (100 mg/kg once daily) was administered to the mice via oral gavage (∼300 μl / mice). We collected all organs involved in the absorption and elimination of imatinib including the liver and the complete GI-tract (esophagus, stomach, small and large intestine and caecum) and subsequently isolated total RNA and protein from these tissues. We performed mRNA and miRNA profiling using mouse genome 430 PM (Affymetrix) and LNA-modified oligonucleotide arrays (Exiqon), respectively, and examined the expression of >80 transporter genes using the RT2 Profiler PCR array system (SABiosciences). Prolonged imatinib treatment resulted in the modulation of various intestinal and hepatic drug transporters and clearly changed the mRNA and miRNA profiles of ADME-involved organs. Apart from the imatinib-associated transporters Abcb1a/b, Abcg2, Slc22a1 and Slco1b2, indicating proof of concept, our search identified various other potential imatinib transporter which are currently tested in uptake experiments using transporter-transfected HEK293 cells. In summary, we showed that continuous exposure of mice to daily dosages of imatinib markedly affects the expression of drug transporters and changes the mRNA and miRNA expression profiles in organs involved in uptake, distribution and elimination of imatinib. These imatinib-induced changes may critically affect the PK, efficacy and adverse events of imatinib chemotherapy. Citation Format: Herman Burger, Alexander T. den Dekker, Antonius WM Boersma, Peter de Bruijn, Jaap Verweij, Ron HJ Mathijssen, Erik AC Wiemer. Imatinib-induced modulation of gastrointestinal and hepatic membrane transporters in mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 883. doi:10.1158/1538-7445.AM2013-883