title: 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.
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA.
authors.forename: Ranjeet Prasad
authors.initials: RP
authors.lastname: Dash
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA.
authors.forename: R
authors.initials: R
authors.lastname: Jayachandra Babu
authors.affiliation: Zydus Research Centre, Ahmedabad, 382210, Gujarat, India. nuggehally.srinivas@zyduscadila.com.
authors.forename: Nuggehally R
authors.initials: NR
authors.lastname: Srinivas
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000166:Acridines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D044966:Anti-Retroviral Agents; D000970:Antineoplastic Agents; D044005:Tetrahydroisoquinolines; C083501:Elacridar