Effect of chronic renal failure on the expression and function of rat intestinal P-glycoprotein in drug excretion.
BACKGROUND
In chronic renal failure, the renal excretion of certain drugs is dramatically reduced. To determine whether other routes of drug elimination, such as secretion through the intestinal barrier by intestinal P-glycoprotein can be altered, we compared P-glycoprotein activity, P-glycoprotein protein content, and P-glycoprotein mRNA levels in intestine of control and chronic renal failure rats.


METHODS
Chronic renal failure was surgically induced in rats by partial (7/8) nephrectomy. After 5 weeks, intestinal transport of rhodamine 123, a P-glycoprotein substrate, was carried out using an in vitro model of everted gut sacs. P-glycoprotein protein content was quantified by enzyme-linked immunosorbent assay and P-glycoprotein mRNA expression was evaluated by semi-quantitative reverse transcriptase polymerase chain reaction.


RESULTS
A decrease of intestinal rhodamine 123 transport was observed in chronic renal failure rats, pointing to an inhibition of P-glycoprotein activity. Transport was inhibited in both sham-operated rats and rats with chronic renal failure by verapamil and cyclosporin A, but relative inhibition vs baseline was less marked in chronic renal failure than in sham-operated rats. In contrast, no significant differences in levels of P-glycoprotein protein or mRNA were observed between the two groups.


CONCLUSIONS
Intestinal secretion of rhodamine 123 is mainly mediated by P-glycoprotein. It was reduced in rats with chronic renal failure, reflecting reduced intestinal drug elimination via a decrease in P-glycoprotein transport activity rather than via protein underexpression.
Veau
C
C
Laboratoire de Physiologie-Pharmacie Clinique, UPRES 2706, Faculté de Pharmacie, Châtenay-Malabry, France.
Leroy
C
C
Banide
H
H
Auchère
D
D
Tardivel
S
S
Farinotti
R
R
Lacour
B
B
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000652:urine*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014700:Verapamil / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D020112:Rhodamine 123; D008353:Mannitol; D016572:Cyclosporine; C095122:multidrug resistance protein 3; D003404:Creatinine; D014700:Verapamil