Teriflunomide is a specific and clinically relevant BCRP probe at the blood‐brain barrier (LB591)

Abstract

Background: Disease modifying antirheumatic drug (DMARD’s), leflunomide, is a non‐cytotoxic proliferation inhibitor of mitogen‐stimulated T and B lymphocytes. Leflunomide is a prodrug that undergoes rapid conversion to its active form, teriflunomide.The latter is poorly metabolized and is eliminated mainly through direct biliary excretion of unchanged drug as well as renal excretion of metabolites. It can take several weeks or months for DMARDs to display a clinical effect which often leads to loss of efficacy in patients over time. Resistance to DMARDs may be a multifactorial phenomenon including enhanced drug efflux by ABC transporters. Recently it was reported that leflunomide and its metabolite, teriflunomide, are high‐affinity substrates of BCRP transporter in vitro. Aim: Assess whether teriflunomide can used as a specific and clinically relevant BCRP probe at the blood‐brain barrier, using in vitro and in vivo models. Methods and results: Efflux assays in Caco2 and MDCKII monolayers overexpressing BCRP were used to determine whether teriflunomide transport is BCRP specific in‐vitro. In these systems teriflunomide was successfully transported and could be inhibited by BCRP specific inhibitor Ko143. Subsequently, brain penetration of teriflunomide was tested in anesthetized mice in dual‐probe microdialysis experiments. Comparing teriflunomide levels in dialysate samples from treated and control animals, administration of Ko143 resulted in an increased brain penetration of teriflunomide. Conclusion: Taken together our results are well correlated, and confirmed that BCRP plays an important role in the pharmacokinetics of teriflunomide which meets the criteria for being a clinically relevant BCRP probe.