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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    • "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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    • "ABCC3 is a member of the ATP-binding cassette (ABC) transporters family. ABC transporters are highly expressed in tumor cells where they actively efflux a broad spectrum of anticancer drugs and thus contribute to MDR891011. ABCC3 is a member of the multidrug resistance-associated protein (MRP) subfamily which is involved in MDR. ABCC3 expression has been shown to be higher in NSCLC than that in SCLC12 and ABCC3 expression correlated with decreased sensitivity of lung cancer cells to anticancer drugs (vincristine, etoposide, and cisplatin)13, and especially to methotrexate and doxorubicin in NSCLC1415. "
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    ABSTRACT: Multidrug resistance (MDR) contributes to the failure of chemotherapy and high mortality in non-small cell lung cancer (NSCLC). We aim to identify MDR genes that predict tumor response to chemotherapy. 199 NSCLC fresh tissue samples were tested for chemosensitivity by MTT assay. cDNA microarray was done with 5 samples with highest resistance and 6 samples with highest sensitivity. Expression of ABCC3 mRNA and protein was detected by real-time PCR and immunohistochemisty, respectively. The association between gene expression and overall survival (OS) was examined using Cox proportional hazard regression. 44 genes were upregulated and 168 downregulated in the chemotherapy-resistant group. ABCC3 was one of the most up-regulated genes in the resistant group. ABCC3-positive expression correlated with lymph node involvement, advanced TNM stage, more malignant histological type, multiple-resistance to anti-cancer drugs, and reduced OS. ABCC3 expression may serve as a marker for MDR and predictor for poor clinical outcome of NSCLC.
    Scientific Reports 11/2013; 3:3120. DOI:10.1038/srep03120 · 5.58 Impact Factor
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