![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Division of Experimental Therapy (C.Z., E.v.d.S., E.W., C.V., A.H.S.) and Division of Molecular Biology (K.v.d.W.), The Netherlands Cancer Institute, Amsterdam, The Netherlands
Multidrug resistance protein 2 (MRP2/Mrp2) is a transporter that can influence the absorption, distribution, and elimination of many drugs. Mrp2 knockout mice are being used to study Mrp2 functions in vivo, including pharmacokinetics of drugs. To assess possible species-specific differences between human MRP2 and mouse Mrp2, we generated polarized cell lines expressing mouse Mrp2 and used these to investigate transport of clinically important agents. We also tested the ability of other drugs to modulate MRP2/Mrp2-mediated transport, a phenomenon that can lead to drug-drug interactions. In MDCK cells stably expressing human MRP2 or mouse Mrp2, saquinavir and docetaxel were more efficiently transported by mouse Mrp2, whereas vinblastine was transported better by human MRP2. MRP2/Mrp2-mediated transepithelial transport of several drugs could be stimulated by probenecid and sulfanitran, but stimulation was often more pronounced for human MRP2 than for mouse Mrp2. Interestingly, for some drugs the MRP2 modulator sulfinpyrazone had opposite effects on both transporters, stimulating human MRP2 and inhibiting mouse Mrp2 activity. In vesicular transport studies, transport of estradiol-17β-glucuronide by mouse Mrp2 showed homotropic cooperativity, as previously described for human MRP2. The MRP2 modulators again showed differential effects on estradiol-17β-glucuronide transport, most notably with sulfinpyrazone stimulating human MRP2 and profoundly inhibiting mouse Mrp2 activity. In conclusion, although human and mouse MRP2/Mrp2 have largely overlapping substrate specificities, there are important species differences in the transport efficiency of MRP2 substrates and in the modulation of transport by other compounds. These differences should be taken into account when results obtained in mice are extrapolated to humans.
This article has been cited by other articles:
|
|
 |
|
  S. Hu, Z. Chen, R. Franke, S. Orwick, M. Zhao, M. A. Rudek, A. Sparreboom, and S. D. Baker Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters Clin. Cancer Res., October 1, 2009; 15(19): 6062 - 6069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L.H. Vlaming, Z. Pala, A. van Esch, E. Wagenaar, D. R. de Waart, K. van de Wetering, C. M.M. van der Kruijssen, R. P.J. Oude Elferink, O. van Tellingen, and A. H. Schinkel Functionally Overlapping Roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the Elimination of Methotrexate and Its Main Toxic Metabolite 7-Hydroxymethotrexate In vivo Clin. Cancer Res., May 1, 2009; 15(9): 3084 - 3093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Heredi-Szabo, H. Glavinas, E. Kis, D. Mehn, G. Bathori, Z. Veres, L. Kobori, O. von Richter, K. Jemnitz, and P. Krajcsi Multidrug Resistance Protein 2-Mediated Estradiol-17{beta}-D-glucuronide Transport Potentiation: In Vitro-in Vivo Correlation and Species Specificity Drug Metab. Dispos., April 1, 2009; 37(4): 794 - 801. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Lagas, C. M. M. van der Kruijssen, K. van de Wetering, J. H. Beijnen, and A. H. Schinkel Transport of Diclofenac by Breast Cancer Resistance Protein (ABCG2) and Stimulation of Multidrug Resistance Protein 2 (ABCC2)-Mediated Drug Transport by Diclofenac and Benzbromarone Drug Metab. Dispos., January 1, 2009; 37(1): 129 - 136. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
