Disrupting P-glycoprotein function in clinical settings: what can we learn from the fundamental aspects of this transporter?

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Chung FS, Santiago JS, Jesus MF, Trinidad CV, See MF

Disrupting P-glycoprotein function in clinical settings: what can we learn from the fundamental aspects of this transporter?

Am J Cancer Res. 2016 Aug 1;6(8):1583-98. eCollection 2016.

PubMed ID

27648351 [ View in PubMed

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Abstract

P-glycoprotein is one of the most well-studied drug transporters, significant for its role in cancer multiple drug resistance. However, using P-gp inhibitors with the aim of enhancing the therapeutic efficacy of anti-cancer drugs has led to disappointing outcomes. Furthermore, several lead compounds suggested by in vitro and pre-clinical studies have shown variable pharmacokinetics and therapeutic efficacies when applied in the clinical setting. This review will highlight the need to revisit a sound approach to better design and apply P-gp inhibitors in light of safety and efficacy. Challenges confronting the issue hinge upon myriad studies that do not necessarily represent the heterogeneous target population of this therapeutic approach. The application of P-gp modulators has also been complicated by the promiscuous substrate-binding behaviour of P-gp, as well as toxicities related to its intrinsic presence in healthy tissue. This review capitalizes on information spanning genetics, energetics, and pharmacology, bringing to light some fundamental aspects that ought to be reconsidered in order to improve upon and design the next generation of P-gp inhibitors.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Dofequidar	P-glycoprotein 1	Protein	Humans	Unknown	Inhibitor	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Dofequidar	P-glycoprotein 1	Protein	Humans	Unknown	Inhibitor	Details