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

0090-9556/08/3601-124-128$20.00
DMD 36:124-128, 2008

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Effects of Chronic Renal Failure on Liver Drug Transporters

Judith Naud, Josée Michaud, Francois A. Leblond, Stéphane Lefrancois, Alain Bonnardeaux, and Vincent Pichette

Service de Néphrologie et Centre de Recherche de l'Hôpital Maisonneuve-Rosemont (J.N., J.M., F.A.L., S.L., A.B., V.P.) and Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Québec, Canada (J.N., J.M., V.P.)

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 (P-gp) 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 (Oatp) 2] and in drug extrusion (P-gp and MRP2). Two groups of rats were studied: control and CRF. Oatp2, P-gp, 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 with control, creatinine clearance was reduced by 70% (p < 0.01) in rats with CRF. Protein expression and mRNA levels of P-gp were increased by 25 and 40% (p < 0.01), respectively, in liver from rats with CRF. MRP2 protein expression was identical in both groups, whereas its mRNA levels were increased by 35% (p < 0.01) in CRF rats. Finally, Oatp2 protein expression was reduced by 35%, whereas 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.

Address correspondence to: Dr. Vincent Pichette, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, 5415 boul. de l'Assomption, Montréal, QC, Canada, H1T 2M4. E-mail: vpichette.hmr{at}ssss.gouv.qc.ca




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T. D. Nolin, R. F. Frye, P. Le, H. Sadr, J. Naud, F. A. Leblond, V. Pichette, and J. Himmelfarb
ESRD Impairs Nonrenal Clearance of Fexofenadine but not Midazolam
J. Am. Soc. Nephrol., October 1, 2009; 20(10): 2269 - 2276.
[Abstract] [Full Text] [PDF]


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