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ABC multidrug transporters: Target for modulation of drug pharmacokinetics and drug-drug interactions

Pharmacologie Cellulaire et moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, B- 1200 Brussels, Belgium.
Current drug targets (Impact Factor: 3.6). 11/2010; 12(5):600-20. DOI: 10.2174/138945011795378504
Source: PubMed

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, potentially affecting 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.

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    • "The denomination P-gp usually refers to the protein encoded by MDR1, mdr1a and mdr1b and, therefore, it will be herein followed. The human P-gp is predominantly and physiologically expressed at the apical/luminal membrane of polarized cells in several normal tissues with secretory (small intestine, liver, kidney, adrenal gland) and barrier functions (small intestine, blood–brain barrier, blood–testis barrier, blood–ovarian barrier and placenta ) (Volk et al. 2004; Fromm 2004; Giacomini et al. 2010; Marquez and Van Bambeke 2011). Indeed, P-gp forms a functional barrier that protects the body by actively limiting the absorption and systemic distribution of xenobiotic compounds, and/or increasing their elimination together with xenobiotic-metabolizing enzymes (Löscher and Potschka 2002b; Dantzig et al. 2003; Volk et al. 2004; Fromm 2004; Kwan and Brodie 2005; del Amo et al. 2009). "
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    • "Substrate competition has been reported to have implications in different biochemical processes, including degradation of polymeric carbohydrates [1], plant secondary metabolism [2], metabolic transport [3] [4] [5], signal transduction pathways [6] and gene regulation [7] [8]. All these have in common that different substrates compete for the active site of the same enzyme. "
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