600 Current Drug Targets, 2011, 12, 600-620 1389-4501/11 $58.00+.00 2011 Bentham Science Publishers Ltd. ABC Multidrug Transporters: Target for Modulation of Drug Pharmacokinetics and Drug-Drug Interactions Batrice Marquez and Franoise Van Bambeke* Pharmacologie Cellulaire et molculaire, Louvain Drug Research Institute, Universit Catholique de Louvain, B-1200 Brussels, Belgium Abstract: Nine proteins of the ABC superfamily (P-glycoprotein, 7 MRPs and BCRP) are involved in multidrug transport. Being localised at the surface of endothelial or epithelial cells, they expel drugs back to the external medium (if located at the apical side P-glycoprotein, BCRP, MRP2, MRP4 in the kidney) or to the blood (if located at the basolateral side MRP1, MRP3, MRP4, MRP5), modulating thereby their absorption, distribution, and elimination. In the CNS, most transporters are oriented to expel drugs to the blood. Transporters also cooperate with Phase I/Phase II metabolism enzymes by eliminating drug metabolites. Their major features are (i) their capacity to recognize drugs belonging to unrelated pharmacological classes, and (ii) their redundancy, a single molecule being possibly substrate for different transporters. This ensures an efficient protection of the body against invasion by xenobiotics. Competition for transport is now characterized as a mechanism of interaction between co-administered drugs, one molecule limiting the transport of the other, which potentially affects bioavailability, distribution, and/or elimination. Again, this mechanism reinforces drug interactions mediated by cytochrome P450 inhibition, as many substrates of P-glycoprotein and CYP3A4 are common. Induction of the expression of genes coding for MDR transporters is another mechanism of drug interaction, which could affect all drug substrates of the up-regulated transporter. Overexpression of MDR transporters confers resistance to anticancer agents and other therapies. All together, these data justify why studying drug active transport should be part of the evaluation of new drugs, as recently recommended by the FDA. Keywords: P-glycoprotein, BCRP, MRP, ADME properties, drug-drug interactions. INTRODUCTION The proteins from the ATP-binding cassette (ABC) trans-porters superfamily share as common features a capacity to actively transport molecules through the membranes, and to use ATP hydrolysis as an energy source. They have been classified in seven subfamilies (ABCA to ABCG), according mainly to sequence homologies and structural organization 1. The topology and nomenclature of ABC transporters have been extensively reviewed elsewhere 2-4 and will not be addressed here. Most of the 48 human ABC transporters (without the truncated ABCC13 with still unknown function 5) play a role in the export of physiological substrates (amino acids, peptides, lipids, inorganic ions), but nine of them are rather associated to a Multi-Drug Resistance (MDR) pheno-type, due to their ability to extrude out of the cells a large variety of xenobiotics.1 These are the P-glycoprotein (ABCB1, P-gp), the Multidrug Resistance associated Pro-teins or MRPs (MRP1-MRP7, also referred to as ABCC1-6 and ABCC10), and the Breast Cancer Resistance Protein or BCRP (ABCG2). In addition, the intracellular transporter *Address correspondence to this author at the Unit de Pharmacologie Cellulaire et molculaire, UCL 7370 Avenue Mounier 73, B-1200 Brussels, Belgium; Tel: +32-2-764-73-78; Fax: +32-2-764-73-73; E-mail: francoise.vanbambekeuclouvain.be 1 Transporters involved in drug influx belong to another superfamily of transporters, namely the SLC (Solute-Linked Carrier) family (a family of secondary transporters that comprises the organic anion transporting polypeptides (OATPs), the organic anion transporters (OATs) or the organic cation transporters (OCTs). These also play an important role in drug pharmacokinetics and drug-drug interactions 6, 7 but will not be discussed here. ABCA3 has also been implicated in multidrug resistance in leukemia cells, as it can sequester drugs inside lysosomes 8. The role of these MDR transporters, and of P-gp in par-ticular, is well described in the context of resistance to anticancer drugs 9, 10. Yet, as they are widely distributed in the organism 11, they also play an important role in the modulation of absorption, tissue distribution and elimination of their substrates or in the protection of sanctuaries, like the central nervous system (Fig. 1). MDR ABC transporters are therefore considered as a major intervenient in the phar-macokinetics of many drugs, which can in its turn modulate their pharmacological activity or their toxicity 12-14. A first goal of this paper is to review the current knowledge on the role of MDR ABC transporters in drug transport and its consequences in terms of ADME properties. A striking characteristic of these MDR transporters is the wide variety of apparently non chemically-related substrates they can accommodate. This is not