Article

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.

0 Followers
 · 
181 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multidrug resistance (MDR) occurs in prostate cancer, and this happens when cancer cells resist chemotherapeutic drugs by pumping them out of the cells. MDR inhibitors such as cyclosporine A (CsA) can stop the pumping and enhance the drugs accumulated within the cells. The cellular drug accumulation is monitored using a microfluidic chip mounted on a single cell bioanalyzer. This equipment has been developed to measure accumulation of drugs such as doxorubicin (DOX) and fluorescently labeled paclitaxel (PTX) in single prostate cancer cells. The inhibition of drug efflux on the same prostate cell was examined in drug-sensitive and drug-resistant cells. Accumulation of these drug molecules was not found in the MDR cells, PC-3 RX-DT2R cells. Enhanced drug accumulation was observed only after treating the MDR cell in the presence of 5 μM of CsA as the MDR inhibitor. We envision this monitoring of the accumulation of fluorescent molecules (drug or fluorescent molecules), if Conducted on single patient cancer cells, can provide information for clinical monitoring of patients undergoing chemotherapy in the future.
    ASME 2014 IMECE; 11/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Drug targets in the central nervous system (CNS) are numerous and important for drug therapy, e.g., of epilepsy or pain. Drugs and other xenobiotics as well as nutrients cannot freely cross the blood–brain barrier or freely enter cells across plasma membranes and therefore require transport systems. This overview summarizes the current knowledge on the expression of drug transporters in barriers shielding the CNS from the systemic circulation and as such controlling the pharmacokinetics of drugs in the CNS. The main drug transporter families covered are SLCO, SCL22A, ABCB, and ABCC, as genes of these families code for numerous drug transporters. While knowledge on messenger RNA expression in humans, rats, and mice is remarkable, there is clearly a gap in knowledge on the subcellular expression of transporters in specific cells in the CNS and in the barriers shielding the CNS from the systemic circulation. Recent methodologic developments including synthesis of drugs and endogenous substances for imaging will in the future allow the investigation of the function and physiologic role of transporters in the CNS including difficult-to-access systems such as the choroid plexus.
    Clinical Pharmacokinetics 02/2015; DOI:10.1007/s40262-015-0241-y · 5.49 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In aquatic organisms, such as fish, blood is continually exposed to aquatic contaminants. Multidrug Resistance (MDR) proteins are ubiquitous detoxification membrane pumps, which recognize various xenobiotics. Moreover, their expression is induced by a large class of drugs and pollutants. We have highlighted the co-expression of a mini P-gp of 75 kDa and a P-gp of 140 kDa in the primary culture of brown trout erythrocytes and in the erythrocytes of wild brown trout collected from three rivers in the Auvergne region of France. In vitro experiments showed that benzo[a]pyrene, a highly toxic pollutant model, induced the co-expression of mini-P-gp and P-gp in trout erythrocytes in a dose-dependent manner and relay type response. Similarly, in the erythrocytes of wild brown trout collected from rivers contaminated by a mixture of PAH and other multi-residues of pesticides, mini-P-gp and P-gp were able to modulate their expression, according to the nature of the pollutants. The differential and complementary responses of mini-P-gp and P-gp in trout erythrocytes suggest the existence in blood cells of a real protective network against xenobiotics/drugs. This property could be exploited to develop a blood biomarker of river pollution. Keywords: blood biomarker; erythrocytes; brown trout; mini-P-gp; P-gp; river pollution
    03/2015; 5(1). DOI:10.3390/diagnostics5010010

Preview

Download
10 Downloads
Available from