Abstract
Chronic renal failure (CRF) is associated with an increased bioavailability of drugs by a poorly understood mechanism. One hypothesis is a reduction in the elimination of drugs by the intestine, i.e., drug elimination mediated by protein membrane transporters such as P-glycoprotein (Pgp) and multidrug-resistance-related protein (MRP) 2. The present study aimed to investigate the repercussions of CRF on intestinal transporters involved in drug absorption [organic anion-transportingpolypeptide (Oatp)] and those implicated in drug extrusion (Pgp and MRP2). Pgp, MRP2, MRP3, Oatp2, and Oatp3 protein expression and Pgp, MRP2, and Oatp3 mRNA expression were assessed in the intestine of CRF (induced by five-sixth nephrectomy) and control rats. Pgp and MRP2 activities were measured using the everted gut technique. Rat enterocytes and Caco-2 cells were incubated with sera from control and CRF rats to characterize the mechanism of transporters' down-regulation. Protein expression of Pgp, MRP2, and MRP3 were reduced by more than 40% (p < 0.01) in CRF rats, whereas Oatp2 and Oatp3 expression remained unchanged. There was no difference in the mRNA levels assessed by real-time polymerase chain reaction. Pgp and MRP2 activities were decreased by 30 and 25%, respectively, in CRF rats compared with control (p < 0.05). Uremic sera induced a reduction in protein expression and in activity of drug transporters compared with control sera. Our results demonstrate that CRF in rats is associated with a decrease in intestinal Pgp and MRP2 protein expression and function secondarily to serum uremic factors. This reduction could explain the increased bioavailability of drugs in CRF.
Footnotes
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This work was supported by the Canadian Institute for Health Research and by the Fonds de la Recherche en Santé du Québec. V.P. and J.N. are scholars of the Fonds de la Recherche en Santé du Québec.
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This work was presented in the Master's thesis of J.N. at the Universitéde Montréal, Département de Pharmacologie in December 2005.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.112631.
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ABBREVIATIONS: CRF, chronic renal failure; Pgp, P-glycoprotein; MRP, multidrug resistance-related protein; Oatp, organic anion-transporting polypeptide; Rho-123, rhodamine 123; DIG, digoxigenin; PCR, polymerase chain reaction; CDF, 5-(and-6)-carboxy-2′,7′dichlorofluorescein; CTL, control; Papp, apparent permeability; P450, cytochrome P450.
- Received August 17, 2006.
- Accepted November 27, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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