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 eliminat ion, such as secretion through the intestinal barrier by intestinal P-glyco protein can be altered, we compared P-glycoprotein activity, P-glycoprotein protein content, and P-glycoprotein mRNA levels in intestine of control an d 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 im munosorbent 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 c hronic renal failure rats, pointing to an inhibition of P-glycoprotein acti vity. Transport was inhibited in both sham-operated rats and rats with chro nic renal failure by verapamil and cyclosporin A, but relative inhibition v s baseline was less marked in chronic renal failure than in sham-operated r ats. In contrast, no significant differences in levels of P-glycoprotein pr otein 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 tran sport activity rather than via protein underexpression.