Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs.
BACKGROUND
Biliary excretion is a major elimination route of many drugs and their metabolites. Hepatobiliary elimination is a vectorial process involving uptake transporters in the basolateral hepatocyte membrane, possibly Phase I and Phase II metabolizing enzymes, and ATP-dependent efflux pumps in the apical hepatocyte membrane.


OBJECTIVE
Because many drugs and their metabolites are anions, this review focuses on transporters involved in their hepatocellular uptake (members of the organic anion transporting polypeptide (OATP) family) and biliary elimination (apical conjugate efflux pump ABCC2/MRP2).


METHODS
The molecular and functional characteristics of the human OATP and ABCC/MRP transporters are presented, including a detailed overview of endogenous and drug substrates. Examples illustrate the interplay of transporters with Phase II conjugating enzymes. Model systems to study the vectorial transport of organic anions are also discussed.


CONCLUSIONS
OATP uptake transporters, conjugating enzymes, and ABCC2/MRP2 work in concert to enable the hepatobiliary elimination of anionic drugs and their metabolites. It is increasingly important to understand how genetic variants of these transporters and enzymes influence the interindividual variability of drug elimination.
Nies
Anne T
AT
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Auerbachstrasse 112, 70376 Stuttgart, Germany. anne.nies@ikp-stuttgart.de
Schwab
Matthias
M
Keppler
Dietrich
D
D000818:Animals; D001693:Biological Transport, Active; D002460:Cell Line; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013379:Substrate Specificity; D014162:Transfection
D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations; C000715087:ABCC2 protein, human