Effects of chronic renal failure on liver drug transporters.
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.
Naud
Judith
J
Service de Néphrologie et Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Université de Montréal, Québec, Canada.
Michaud
Josée
J
Leblond
Francois A
FA
Lefrancois
Stéphane
S
Bonnardeaux
Alain
A
Pichette
Vincent
V
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D022781:Hepatocytes / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D027361:Organic Anion Transporters / Q000096:biosynthesis; D004364:Pharmaceutical Preparations / Q000097:blood / Q000378:metabolism* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012235:Rhodamines
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations; D012235:Rhodamines; C503597:Slco1a4 protein, rat