P-glycoprotein Inhibition: The Past, the Present and the Future

Richard      A.J. Darby; Richard      Callaghan; Roisin      M. McMahon

doi:10.2174/138920011798357006

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 chemists wish list for the paradigmatic P-gp inhibitor molecule and examine the possible future strategies that could be implemented to achieve its design.

Keywords: ABC transporter, chemotherapy, cytochrome P450, drug metabolism, Multidrug resistance, P-gp., MDR1, xenobiotic, (UDP-glucoronosyl-transferase), bio-transformation