title: P-glycoprotein inhibition: the past, the present and the future.
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.
authors: Medical Sciences Division, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK. richard.darby@ndcls.ox.ac.uk
authors: Richard A J
authors: RA
authors: Darby
authors: Richard
authors: R
authors: Callaghan
authors: Roisin M
authors: RM
authors: McMahon
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D003577:Cytochrome P-450 Enzyme System