Veau C, Leroy C, Banide H, Auchère D, Tardivel S, Farinotti R, Lacour B
Laboratoire de Physiologie-Pharmacie Clinique, UPRES 2706, Faculté de Pharmacie, Châtenay-Malabry, France.
Nephrol Dial Transplant. 2001 Aug;16(8):1607-14. doi: 10.1093/ndt/16.8.1607.
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.
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.
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.
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.
在慢性肾衰竭中，某些药物的肾脏排泄显著减少。为了确定其他药物消除途径，如肠道P-糖蛋白通过肠屏障的分泌是否会改变，我们比较了对照组和慢性肾衰竭大鼠肠道中P-糖蛋白活性、P-糖蛋白蛋白含量和P-糖蛋白mRNA水平。
通过部分（7/8）肾切除术手术诱导大鼠发生慢性肾衰竭。5周后，使用外翻肠囊体外模型进行P-糖蛋白底物罗丹明123的肠道转运。通过酶联免疫吸附测定法定量P-糖蛋白蛋白含量，并通过半定量逆转录聚合酶链反应评估P-糖蛋白mRNA表达。
在慢性肾衰竭大鼠中观察到肠道罗丹明123转运减少，表明P-糖蛋白活性受到抑制。维拉帕米和环孢素A对假手术大鼠和慢性肾衰竭大鼠的转运均有抑制作用，但慢性肾衰竭大鼠相对于基线的相对抑制作用不如假手术大鼠明显。相比之下，两组之间P-糖蛋白蛋白或mRNA水平未观察到显著差异。
罗丹明123的肠道分泌主要由P-糖蛋白介导。在慢性肾衰竭大鼠中其减少，反映出通过P-糖蛋白转运活性降低而非蛋白表达不足导致肠道药物消除减少。
