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Eukaryotic transport proteins in drug action and resistance.

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There is a rapidly growing consensus in the drug development community, in both academic and pharmaceutical sectors, that transporters profoundly impact on the distribution, toxicology and effectiveness of drugs. It is now clear that pharmacokinetics and cellular uptake of drugs and their metabolites are far ...

There is a rapidly growing consensus in the drug development community, in both academic and pharmaceutical sectors, that transporters profoundly impact on the distribution, toxicology and effectiveness of drugs. It is now clear that pharmacokinetics and cellular uptake of drugs and their metabolites are far more determined by transporter action, and less by simple cross-membrane diffusion, then once assumed, and codified in the Lipinski rules for drug-like molecules. As a result, there has been a very welcome surge of published research and reviews on drug transporters in recent years. Much of this research aims to better understand, and ultimately predict, drug distribution, and drug-drug interaction through competition at the level of specific transporters, in the human system. Both the U.S. Food and Drug Administration and the European Medicines Agency now directly address transporter studies in their guidelines for drug interaction studies. In addition to the pharmacokinetic issues of absorption, distribution, metabolism and excretion (ADME), and their impact on toxicology and drug efficacy, transporters on target cells have a profound effect on drug efficacy and resistance. Whether the target is human cancer cell or an invading micro-organism, transporters usually determine the effective intracellular concentration of the active compound, how rapidly this concentration is achieved, and whether the drug is able to achieve a higher concentration in the cell than in circulation. The most common single form of drug resistance is the loss, mutation or non-expression of a target cell transporter, or the expression of an efflux transporter for the drug. It is thus ultimately the interplay between the ‘ADME transporters’ and the target cell transporters that determines the concentration of the active compound at the target level, and thereby drug efficacy. It is therefore important to bring experts on the various drug transporters together in a discussion forum that allows exchanges of expertise, methodologies, expression systems etc. Frontiers in Pharmacology provides an excellent platform for direct interaction between researchers working on the various subcategories of human drug transporters, such as multi-drug resistance pumps, Organic Cation Transporters, Breast Cancer Resistance Protein, Organic Anion Transporters, and those studying drug (resistance) transporters on target cells such as cancer cells, and on pathogenic fungi, protozoa and bacteria.


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