P10.21.A THE ABCB1/ABCG2 INHIBITOR ELACRIDAR IS A MORE POTENT PHARMACOENHANCER COMPARED TO TARIQUIDAR FOR TREATMENT OF INTRACRANIAL TUMORS WITH SMALL MOLECULE DRUGS

Abstract

Abstract BACKGROUND The blood-brain barrier (BBB) is a major hurdle to successful pharmacotherapy of brain tumors. ABCB1 and ABCG2 are efflux transporters that are expressed in brain tumor vessels and reduce the uptake of many small molecule drugs. Elacridar and tariquidar are both dual ABCB1 and ABCG2 inhibitors. We aim to improve pharmacotherapy of brain cancer by concomitant use of potentially effective drugs with elacridar. Since tariquidar has mostly been used to assess the effects of ABC-transporters on brain uptake in human studies with PET tracers, we decided to compare both agents in our rodent models. MATERIAL AND METHODS We used Abcg2;Abcb1a/b double knockout (DKO), Abcb1a/b KO, Abcg2 KO and wild-type mice receiving a cocktail of 7 model drugs at a fixed low dose in combination with elacridar or tariquidar at a range of doses. Drugs were given by 3-h infusion. DKO mice are the reference for complete inhibition, while single KO mice allow interrogation of the remaining transporter in case of dual substrate drugs. Brain and plasma levels were measured by LC-MS/MS. RESULTS Complete inhibition of Abcb1 by elacridar was achieved when the plasma level is about 1.0 μM. However, a much higher plasma level (>4 μM) of tariquidar was needed. Inhibition of Abcg2 was more difficult. For erlotinib and palbociclib about 1.0 μM of elacridar was sufficient, but other more profound Abcg2 substrate drugs never reached the B/P ratios achieved in reference to DKO mice, even at 4 μM. Strikingly, tariquidar could not enhance the brain uptake of ABCG2-subtrate drugs in Abcb1a/b KO mice. The B/P ratio of elacridar in DKO mice was 6. Elacridar improved its own brain distribution in WT mice, achieving steady-state B/P ratios at plasma level above 1.4 μM. The B/P ratio of tariquidar in DKO mice was about 2, while in WT and Abcb1a/b KO mice was 0.3 and did not increase even at plasma concentration >8 μM. Only in Abcg2 KO mice, the B/P ratio increased to levels of DKO mice at tariquidar plasma levels of > 6 μM. CONCLUSION Elacridar is a much more potent inhibitor of Abcb1a/b and Abcg2 at the BBB. Elacridar can act as a pharmaco-enhancer of ABCB1 substrate drugs and weaker ABCG2 substrates. Tariquidar will enhance the brain penetration of ABCB1 substrates, but full inhibition is only achieved at levels above those reported in human subjects. The efflux of tariquidar by Abcg2 at the BBB severely compromises the usefulness of tariquidar as a pharmaco-enhancer for brain delivery.