RGD Reference Report - Down-regulation of intestinal drug transporters in chronic renal failure in rats. - Rat Genome Database

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Down-regulation of intestinal drug transporters in chronic renal failure in rats.

Authors: Naud, J  Michaud, J  Boisvert, C  Desbiens, K  Leblond, FA  Mitchell, A  Jones, C  Bonnardeaux, A  Pichette, V 
Citation: Naud J, etal., J Pharmacol Exp Ther. 2007 Mar;320(3):978-85. Epub 2006 Nov 29.
RGD ID: 2301067
Pubmed: PMID:17135344   (View Abstract at PubMed)
DOI: DOI:10.1124/jpet.106.112631   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  

Objects Annotated

Genes (Rattus norvegicus)
Abcb1a  (ATP binding cassette subfamily B member 1A)
Abcb1b  (ATP-binding cassette, sub-family B member 1B)
Abcc2  (ATP binding cassette subfamily C member 2)
Abcc3  (ATP binding cassette subfamily C member 3)

Genes (Mus musculus)
Abcb1a  (ATP-binding cassette, sub-family B member 1A)
Abcb1b  (ATP-binding cassette, sub-family B member 1B)
Abcc2  (ATP-binding cassette, sub-family member 2)
Abcc3  (ATP-binding cassette, sub-family C member 3)

Genes (Homo sapiens)
ABCB1  (ATP binding cassette subfamily B member 1)
ABCC2  (ATP binding cassette subfamily C member 2)
ABCC3  (ATP binding cassette subfamily C member 3)


Additional Information