P-glycoprotein inhibition: The past, the present and the future

Richard A.J. Darby*, Richard Callaghan, Róisín M. McMahon

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

80 Citations (Scopus)

Abstract

The multidrug resistant phenotype of cancer cells can often result from the over-production of a number of ATP binding cassette (ABC) transporters, including P-glycoprotein (P-gp). These multidrug efflux transporters expel administered anti-cancer drugs from the cancer cell, preventing sufficient intracellular drug accumulation and ultimately, drug efficacy. The co-administration of compounds that can impede the efflux of chemotherapeutic agents by these ABC transporters can concomitantly modulate various cytochrome P450 (CYP450) enzymes, consequently impacting upon anti-cancer drug metabolism. This can further result in unfavourable drug-drug interactions and altered pharmacokinetic properties of the administered anti-cancer drugs with knock-on adverse cytotoxic side effects. This review will discuss some of the P-gp inhibitors designed and employed to date, as well as expressing our views of the shortcomings of their design strategy. We present a medicinal chemist's wish list for the paradigmatic P-gp inhibitor molecule and examine the possible future strategies that could be implemented to achieve its design.

Original languageEnglish
Pages (from-to)722-731
Number of pages10
JournalCurrent Drug Metabolism
Volume12
Issue number8
DOIs
Publication statusPublished - Oct 2011
Externally publishedYes

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