Abstract
Chronic renal failure (CRF) leads to decreased drug renal clearance due to a reduction in the glomerular filtration rate. However, little is known about how renal failure affects renal metabolism and elimination of drugs. Because both depend on the activity of uptake and efflux by renal transporters as well as enzymes in tubular cells, the purpose of this study was to investigate the effects of CRF on the expression and activity of select renal drug transporters and cytochrome P450. Two groups of rats were studied: control and CRF (induced by 5/6 nephrectomy). Compared with control rats, we observed reductions in the expression of both protein and mRNA of Cyp1a, sodium-dependent phosphate transport protein 1, organic anion transporter (Oat)1, 2, and 3, OatK1/K2, organic anion-transporting polypeptide (Oatp)1 and 4c1, P-glycoprotein, and urate transporter 1, whereas an induction in the protein and mRNA expression of Mrp2, 3, and 4 and Oatp2 and 3 was observed. Cyp3a expression remained unchanged. Similar results were obtained by incubating a human proximal tubule cell line (human kidney-2) with sera from CRF rats, suggesting the presence of uremic modulators. Finally, the renal elimination of [3H]digoxin and [14C]benzylpenicillin was decreased in CRF rats, compared with controls, as shown by a 4- and 9-fold accumulation, respectively, of these drugs in kidneys of rats in CRF. Our results demonstrate that CRF affects the expression and activity of several kidney drug transporters leading to the intrarenal accumulation of drugs and reduced renal clearance that could, at least partially, explain the tubular toxicity of many drugs.
Footnotes
This work was supported in part by the Canadian Institute for Health Research; La Fondation Hôpital Maisonneuve-Rosemont (La Néphrologie et son Impact); Le Consortium de Néphrologie de l'Université de Montreal; and Astellas Pharma Canada Inc. V.P., M.-J.H., S.L., and M.R. were supported by career awards from Fonds de la Recherche en Santé du Québec.
The opinions expressed in this paper are those of the authors. Astellas Pharma Inc. had no role in the design of the study, in the data analysis and interpretation, and in the manuscript preparation.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039115.
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ABBREVIATIONS:
- CRF
- chronic renal failure
- CTL
- control
- P450
- cytochrome P450
- Mrp
- multidrug resistance-related protein
- Npt1
- sodium-dependent phosphate transport protein 1
- Oat
- organic anion transporter
- Oatp
- organic anion-transporting polypeptide
- Papp
- apparent permeability
- PCR
- polymerase chain reaction
- P-gp
- P-glycoprotein
- PMSF
- phenylmethylsulfonyl fluoride
- URAT
- urate transporter
- HK-2
- human kidney-2
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase.
- Received February 24, 2011.
- Accepted April 27, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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