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The blood-brain barrier (BBB) is a formidable hurdle to successful pharmacotherapy of intracranial diseases. ABCB1 and ABCG2 are efflux transporters that play an important role in the BBB, keeping substances out of the brain. Elacridar and tariquidar are third-generation ABCB1-inhibitors developed for treatment of multidrug-resistant tumors. Later, they were shown to also inhibit ABCG2. We aim to improve pharmacotherapy of brain cancer by concomitant use of potentially effective drugs with elacridar. This study was undertaken to determine the relationship between the plasma concentration of the inhibitor and the brain-to-plasma (B/P) ratio of (model) substrate drugs in order to assess which type of drug may best qualify taking into account clinically achievable plasma levels of the inhibitor. We used Abcg2;Abcb1a/b double knockout (DKO), Abcb1a/b KO, Abcg2 KO and wild-type mice receiving a cocktail of 9 drugs at a fixed low dose plus a range of doses of inhibitor by 3-h intraperitoneal infusion to achieve steady-state conditions. DKO mice are the reference for complete inhibition, while single KO mice allow interrogation of the other transporter when using dual substrate drugs. Complete inhibition of Abcb1 by elacridar requires plasma levels of about 1000 nM. Inhibition of Abcg2 is more difficult. For erlotinib and palbociclib about 1000 nM of elacridar is sufficient, but other more profound substrate drugs (e.g. vemurafenib and afatinib) do not reach the B/P ratios achieved in DKO mice, even at 4000 nM. The improvement in B/P ratio that can be reached differs per substrate. Compounds like palbociclib benefit markedly from elacridar with B/P ratios rising from 0.25 to 7, whereas others (e.g. erlotinib and dasatinib) increase from about 0.10 to only 0.40. Thus, elacridar is an efficient pharmaco-enhancer of ABCB1 substrates and weaker ABCG2 substrates, but is not able to improve brain delivery of drugs that are profound ABCG2 substrates.

neuro-oncology

EXTH-72. CONTINUOUS INFUSION STUDIES REVEAL THE POTENCY OF ELACRIDAR TO ACT AS A PHARMACO-ENHANCER FOR TREATMENT OF INTRACRANIAL DISEASES BY INHIBITING ABCB1 AND ABCG2 AT THE BLOOD-BRAIN BARRIER