1. Curr Drug Targets. 2011 May;12(5):600-20.

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

Marquez B, Van Bambeke F.

Pharmacologie Cellulaire et moléculaire, Louvain Drug Research Institute,
Université Catholique de Louvain, B- 1200 Brussels, Belgium.

Comment in
    Curr Drug Targets. 2011 May;12(5):598-9.

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.

PMID: 21039335  [PubMed - in process]