Down-regulation of intestinal drug transporters in chronic renal failure in rats.
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.
Naud
Judith
J
Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, 5415 Boulevard de l'Assomption, Montreal, Quebec, Canada H1T 2M4.
Michaud
Josée
J
Boisvert
Caroline
C
Desbiens
Karine
K
Leblond
Francois A
FA
Mitchell
Andrew
A
Jones
Christine
C
Bonnardeaux
Alain
A
Pichette
Vincent
V
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis; D000818:Animals; D001835:Body Weight; D018938:Caco-2 Cells; D017077:Culture Media, Conditioned; D004195:Disease Models, Animal; D015536:Down-Regulation; D020895:Enterocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
C000715087:ABCC2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D017077:Culture Media, Conditioned; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; D012333:RNA, Messenger