PET-CT imaging with [18F]-gefitinib to measure Abcb1a/1b (P-gp) and Abcg2 (Bcrp1) mediated drug-drug interactions at the murine blood-brain barrier

Introduction: The efflux transporters P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) are expressed at the blood-brain barrier (BBB), and can limit the access of a wide range of drugs to the brain. In this study we developed a PET-CT imaging method for non-invasive, quantitative analysis of the effect of ABCB1 and ABCG2 on brain penetration of the anti-cancer drug gefitinib, and demonstrated the applicability of this method for identification and quantification of potential modulators of ABCB1 and ABCB2 using the dual inhibitor elacridar. Methods: In vitro cellular accumulation studies with [14C]-gefitinib were conducted in LLC-PK1, MDCKII, and the corresponding ABCB1/Abcb1a and ABCG2/Abcg2 overexpressing cell lines. Subsequently, in vivo brain penetration of [18F]-gefitinib was quantified by PET-CT imaging studies in wild-type, Abcg2-/-, Abcb1a/1b-/-, and Abcb1a/1b;Abcg2-/- mice. Results: In vitro studies showed that [14C]-gefitinib is a substrate of the human ABCB1 and ABCG2 transporters. After i.v. administration of [18F]-gefitinib (1mg/kg), PET-CT imaging showed 2.3-fold increased brain levels of [18F]-gefitinib in Abcb1a/1b;Abcg2-/- mice, compared to wild-type. Levels in single knockout animals were not different from wild-type, showing that Abcb1a/1b and Abcg2 together limit access of [18F]-gefitinib to the brain. Furthermore, enhanced brain accumulation of [18F]-gefitinib after administration of the ABCB1 and ABCG2 inhibitor elacridar (10 mg/kg) could be quantified with PET-CT imaging. Conclusions: PET-CT imaging with [18F]-gefitinib is a powerful tool to non-invasively assess potential ABCB1- and ABCG2-mediated drug-drug interactions (DDIs) in vivo. Advances in knowledge and implications for patient care: This minimally-invasive, [18F]-based PET-CT imaging method shows the interplay of ABCB1 and ABCG2 at the BBB in vivo. The method may be applied in the future to assess ABCB1 and ABCG2 activity at the BBB in humans, and for personalized treatment with drugs that are substrates of ABCB1 and/or ABCG2. © 2015 Elsevier Inc.