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: 3.02). 11/2010; 12(5):600-20. DOI: 10.2174/138945011795378504
Source: PubMed


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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    • "anticancer, anti-human immunodeficiency virus drugs, synthetic steroids, antibiotics) and environmental toxins (e.g. bisphenol A—BPA, ivermectin) (Marquez and Van Bambeke, 2011; Iqbal et al., 2012; Mazur et al., 2012; Table I). ABC transporters play a critical role in barrier-tissues such as the placenta (Table II), bloodbrain barrier (BBB) and blood-testis barrier (BTB). "
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    ABSTRACT: Background: The transmembrane ATP-binding cassette (ABC) transporters actively efflux an array of clinically relevant compounds across biological barriers, and modulate biodistribution of many physiological and pharmacological factors. To date, over 48 ABC transporters have been identified and shown to be directly and indirectly involved in peri-implantation events and fetal/placental development. They efflux cholesterol, steroid hormones, vitamins, cytokines, chemokines, prostaglandins, diverse xenobiotics and environmental toxins, playing a critical role in regulating drug disposition, immunological responses and lipid trafficking, as well as preventing fetal accumulation of drugs and environmental toxins. Methods: This review examines ABC transporters as important mediators of placental barrier functions and key reproductive processes. Expression, localization and function of all identified ABC transporters were systematically reviewed using PubMed and Google Scholar websites to identify relevant studies examining ABC transporters in reproductive tissues in physiological and pathophysiological states. Only reports written in English were incorporated with no restriction on year of publication. While a major focus has been placed on the human, extensive evidence from animal studies is utilized to describe current understanding of the regulation and function of ABC transporters relevant to human reproduction. Results: ABC transporters are modulators of steroidogenesis, fertilization, implantation, nutrient transport and immunological responses, and function as 'gatekeepers' at various barrier sites (i.e. blood-testes barrier and placenta) against potentially harmful xenobiotic factors, including drugs and environmental toxins. These roles appear to be species dependent and change as a function of gestation and development. The best-described ABC transporters in reproductive tissues (primarily in the placenta) are the multidrug transporters p-glycoprotein and breast cancer-related protein, the multidrug resistance proteins 1 through 5 and the cholesterol transporters ABCA1 and ABCG1. Conclusions: The ABC transporters have various roles across multiple reproductive tissues. Knowledge of efflux direction, tissue distribution, substrate specificity and regulation of the ABC transporters in the placenta and other reproductive tissues is rapidly expanding. This will allow better understanding of the disposition of specific substrates within reproductive tissues, and facilitate development of novel treatments for reproductive disorders as well as improved approaches to protecting the developing fetus.
    Human Reproduction Update 11/2015; DOI:10.1093/humupd/dmv049 · 10.17 Impact Factor
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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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    ABSTRACT: Multidrug resistance (MDR) represents one of the major problems in pharmacotherapy of important diseases (e.g., cancer, epilepsy). Although many factors may contribute to the development of MDR phenotype, the increased expression and/or functional activity of P-glycoprotein (P-gp; active drug efflux transporter) across the cell membrane has been recognized as the main one. Therefore, a great attention has been given to the search of P-gp inhibitors as therapeutic agents to reverse the MDR mediated by P-gp. Since the chemical entities identified over the last three decades as potential P-gp inhibitors did not show suitable pharmacological properties, more recently herbal components, such as flavonoid compounds, have gained a great interest as safe P-gp inhibitors. The interest in flavonoids as P-gp inhibitors is increasing due to their potential favourable characteristics, including selectivity and noncytotoxic effects. Flavonoids integrate the third-generation non-pharmaceutical category of P-gp inhibitors, and some of them exhibited effects comparable to those of the classic P-gp inhibitors. In fact, some flavonoids found in foods and beverages of herbal origin appear to be quite promising to inhibit the P-gp– mediated drug efflux, indicating their potential value to enhance the systemic/cellular bioavailability of P-gp drug substrates when administrated in cotherapy. This review paper summarizes the current evidence of P-gp inhibitory effects produced by flavonoids, taking into account studies performed in cell-based in vitro models, in vivo animal models and clinical trials.
    Phytochemistry Reviews 04/2014; 14(2). DOI:10.1007/s11101-014-9358-0 · 2.41 Impact Factor
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    • "Vinca alkaloids, actinomycin D, taxol, antracyclines), calcium channel blockers (e.g. verapamil)3561112141516171819202122. Due to this property, P-gp is involved in the natural defence mechanisms of cells, tissues and organs, and forms an essential part of the innate defence system known as “chemo-immunity”3. "
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    ABSTRACT: Blood is a site of physiological transport for a great variety of molecules, including xenobiotics. Blood cells in aquatic vertebrates, such as fish, are directly exposed to aquatic pollution. P-gp are ubiquitous "membrane detoxification proteins" implicated in the cellular efflux of various xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs), which may be pollutants. The existence of this P-gp detoxification system inducible by benzo [a] pyrene (BaP), a highly cytotoxic PAH, was investigated in the nucleated erythrocytes of brown trout. Western blot analysis showed the expression of a 140-kDa P-gp in trout erythrocytes. Primary cultures of erythrocytes exposed to increasing concentrations of BaP showed no evidence of cell toxicity. Yet, in the same BaP-treated erythrocytes, P-gp expression increased significantly in a dose-dependent manner. Brown trout P-gp erythrocytes act as membrane defence mechanism against the pollutant, a property that can be exploited for future biomarker development to monitor water quality.
    Scientific Reports 12/2013; 3:3422. DOI:10.1038/srep03422 · 5.58 Impact Factor
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