Therapeutic Potential and Utility of Elacridar with Respect to P-glycoprotein Inhibition: An Insight from the Published In Vitro, Preclinical and Clinical Studies

Abstract

The occurrence of efflux mechanisms via Permeability-glycoprotein (P-gp) recognized as an important physiological process impedes drug entry or transport across membranes into tissues. In some instances, either low oral bioavailability or lack of brain penetration has been attributed to P-gp mediated efflux activity. Therefore, the objective of development of P-gp inhibitors was to facilitate the attainment of higher drug exposures in tissues. Many third-generation P-gp inhibitors such as elacridar, tariquidar, zosuquidar, etc. have entered clinical development to fulfil the promise. The body of evidence from in vitro and in vivo preclinical and clinical data reviewed in this paper provides the basis for an effective blockade of P-gp efflux mechanism by elacridar. However, clinical translation of the promise has been elusive not just for elacridar but also for other P-gp inhibitors in this class. The review provides introspection and perspectives on the lack of clinical translation of this class of drugs and a broad framework of strategies and considerations in the potential application of elacridar and other P-gp inhibitors in oncology therapeutics.

Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma

“…Everolimus provides P-gp blockade at a higher dose. Previous work has established that dasatinib is a substrate for the efflux proteins P-gp and BCRP (21)(22)(23)(24). As P-gp is probably the predominant substrate affecting CNS efflux (14), we focused our attention on P-gp.…”

Targeting Lysosomes in Cancer as Promising Strategy to Overcome Chemoresistance—A Mini Review

“…A prominent pathway, however, is linked to aberrant drug efflux mediated by the drug transporter P-glycoprotein (P-gp), an ATP-dependent efflux pump (17). Despite intensive research, all clinical trials evaluating P-gp inhibitors failed to date (18).…”

Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1

“…Small-molecule, third-generation inhibitors, including zosuquidar, tariquidar, and elacridar ( 19 – 21 ), have shown potential in model systems for coadministration with various anticancer agents. However, antibody- and small-molecule inhibitor–based strategies have not been successfully utilized clinically ( 22 , 23 ), emphasizing the need for designing more effective therapeutic and diagnostic strategies targeting ABCB1 expression and inhibition.…”