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Metabolism of ATP-binding cassette drug transporter inhibitors: complicating factor for multidrug resistance.

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Author: Cnubben, N.H. · Wortelboer, H.M. · Zanden, J.J. van · Rietjens, I.M. · Bladeren, P.J. van
Type:article
Date:2005
Institution: TNO Kwaliteit van Leven
Source:Expert opinion on drug metabolism & toxicology., 2, 1, 219-232
Identifier: 238623
Keywords: Health Pharmacology · Physiological Sciences · ABC transporter · cyclosporin derivative · dibenzo[a,d]cycloheptene derivative · glycoprotein P · quinoline derivative · valspodar · zosuquidar · drug antagonism · drug design · drug effect · genetics · human · metabolism · multidrug resistance · review · RNA interference · transport at the cellular level · ATP-Binding Cassette Transporters · Biological Transport · Cyclosporins · Dibenzocycloheptenes · Drug Design · Drug Resistance, Multiple · Humans · P-Glycoproteins · Quinolines · RNA Interference

Abstract

Membrane transport proteins belonging to the ATP-binding cassette (ABC) family of transport proteins play a central role in the defence of organisms against toxic compounds, including anticancer drugs. However, for compounds that are designed to display a toxic effect, this defence system diminishes their effectiveness. This is typically the case in the development of cellular resistance to anticancer drugs. Inhibitors of these transporters are thus potentially useful tools to reverse this transporter-mediated cellular resistance to anticancer drugs and, eventually, to enhance the effectiveness of the treatment of patients with drug-resistant cancer. This review highlights the various types of inhibitors of several multidrug resistance-related ABC proteins, and demonstrates that the metabolism of inhibitors, as illustrated by recent data obtained for various natural compound inhibitors, may have considerable implications for their effect on drug transport and their potential for treatment of drug resistance.