Abstract
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Objectives P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) regulate the intracerebral concentration of various drugs by acting as efflux pumps at the blood-brain barrier (BBB). Co-medication of drugs may result in competition for, or inhibition of efflux transporters leading to increased drug concentrations and toxicity in the brain. Here, we present a quantitative, generic method based on preclinical PET-imaging with [18F]-gefitinib to predict whether a drug is involved in these transporter-mediated drug-drug interactions (DDI) at the BBB.
Methods Wild-type, P-gp, Bcrp1, and P-gp;Bcrp1 knockout mice were i.v. injected with [18F]-gefitinib and dynamic PET scans were acquired for 60 min, followed by CT. An i.v. dose of the dual P-gp and BCRP modulator elacridar (10 mg/kg) or vehicle was administered 15 min prior to tracer injection. ROIs for quantification of [18F]-gefitinib uptake in the brain were determined based on PET/CT fusion images generated with the Philips IMALYTICS software.
Results Wild-type, P-gp, and Bcrp1 ko mice showed comparable brain uptake of [18F]-gefitinib, while brain uptake was increased 2-3 fold in the double ko mice. Pretreatment with the dual P-gp/BCRP inhibitor elacridar resulted in a significant increase of brain uptake in wild-type, P-gp, and Bcrp1 ko mice, while uptake in the double ko mice remained unchanged. The results indicate that [18F]-gefitinib is actively pumped out of the brain by both P-gp and Bcrp1, and that the absence of a single transporter can be compensated. Furthermore, elacridar-induced inhibition of P-gp/BCRP could be quantified by PET imaging with [18F]-gefitinib demonstrating the potential of this compound to cause DDI.
Conclusions We conclude that [18F]-gefitinib PET is a useful tool to non-invasively analyze potential P-gp and BCRP mediated DDIs in vivo. Combining such quantitative PET imaging data with in vitro human drug transporter assays and PBPK-modeling could provide a powerful approach to predict drug pharmacokinetics in humans