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Drug Metabolism and Disposition Fast Forward
First published on October 16, 2007; DOI: 10.1124/dmd.107.018192

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Received for publication August 16, 2007.
Revised October 11, 2007.
Accepted for publication October 11, 2007.

Effects of chronic renal failure on liver drug transporters

Judith Naud 1, Josee Michaud 1, Francois A Lebond 1, Stephane Lefrancois 1, Alain Bonnardeaux 1, Vincent Pichette 2*

1 Centre de recherche Hopital Maisonneuve-Rosemont 2 Centre de recherche Hopital Maissonneuv-Rosemont

* Address correspondence to: E-mail: vpichette.hmr{at}ssss.gouv.qc.ca

Abstract

Chronic renal failure (CRF) is associated with a decrease in liver drug metabolism, particularly mediated by the cytochrome P450. CRF also impedes intestinal drug transporters (mainly P-glycoprotein [Pgp] and multidrug resistance protein [MRP]). However, very few studies have evaluated the effects of CRF on liver drug transport. The present study aimed to investigate the repercussions of CRF on liver drug transporters involved in hepatic uptake (organic anion-transporting-polypeptide [Oatp2]) and in drug extrusion (Pgp and MRP2). Two groups of rats were studied: control and CRF. Oatp2, Pgp and MRP2 protein expressions and mRNA levels, as well as some of their metabolic activity were assessed. The effects of CRF serum on drug transporters were also evaluated in cultured hepatocytes. Compared to control, creatinine clearance was reduced by 70% (p<0.01) in rats with CRF. Protein expression and mRNA levels of Pgp were increased by 25% and 40% (p<0.01), respectively, in liver from rats with CRF. MRP2 protein expression was identical in both groups, while its mRNA levels were increased by 35% (p<0.01) in CRF rats. Finally, Oatp2 protein expression was reduced by 35% while its mRNA levels remained unchanged. Similar results were obtained when hepatocytes were incubated with uremic serum. In conclusion, CRF is associated with a decrease in liver transporters involved in drug absorption and an increase in those involved in drug extrusion. Uremic mediators appear to be responsible for these modifications.


Key words: ABC transporters, biliary excretion, drug clearance, hepatocytes, organic anion transport, p-glycoprotein


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[Abstract] [Full Text] [PDF]


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