The ABCB1/ABCG2 inhibitor elacridar is a more potent pharmacoenhancer compared to tariquidar for treatment of intracranial tumors with small molecule drugs

Background: The blood-brain barrier (BBB) is a major hurdle to successful pharmacotherapy of brain tumors. ABCB1 and ABCG2 are efflux transporters that expressed in tumor vessels reduce the uptake many small molecule drugs. Elacridar tariquidar both dual inhibitors. We aim improve cancer by concomitant use potentially effective drugs with elacridar. Since has mostly been used assess effects ABC-transporters on human studies PET tracers, we decided compare agents our rodent models. determined relationship between plasma concentration inhibitor brain-to-plasma (B/P) ratio substrate Materials methods: Abcg2;Abcb1a/b double knockout (DKO), Abcb1a/b KO, Abcg2 KO wild-type mice receiving cocktail 7 model at fixed low dose combination elacridar or range doses. Dugs were given 3-h infusion. DKO reference for complete inhibition, while single allow interrogation remaining transporter case Brain levels measured LC-MS/MS. Results: Complete inhibition Abcb1 was achieved when level about 1.0 μM. However, much higher (>4 μM) needed. Inhibition more difficult. For erlotinib palbociclib μM sufficient, but other profound (e.g. vemurafenib afatinib) never reached B/P ratios mice, even not 4 Strikingly, able marginally enhance ABCG2-subtrate mice. 6. improved its own distribution WT achieving steady-state above 1.4 2. 0.3 did increase >8 Only increased > 6 It appears BBB severely compromises usefulness as pharmaco-enhancer delivery. Conclusions: Thus, potent BBB. can act weaker substrates, suited delivery substrates. Tariquidar will penetration full only those reported subjects. completely fails inhibit No conflict interest.