Leblond F A, Giroux L, Villeneuve J P, Pichette V
Service de Néphrologie et Centre de Recherche Guy-Bernier, Hopital Maisonneuve-Rosemont, Faculté de Médecine, Université de Montréal, Québec, Canada.
Drug Metab Dispos. 2000 Nov;28(11):1317-20.
Chronic renal failure (CRF) is associated with a decrease in renal excretion of drugs, but its effects on the liver metabolism of xenobiotics are poorly defined. The objectives of this study were to determine the effects of CRF on hepatic cytochrome P450 (CYP450) and its repercussions on in vivo hepatic metabolism of drugs. Two groups of rats were studied: control paired-fed and CRF. CRF was induced by subtotal nephrectomy. Total CYP450 activity and protein expression of several CYP450 isoforms (CYP1A2, CYP2C11, CYP3A1, CYP3A2) were assessed in liver microsomes. In vivo cytochrome P450 activity was evaluated with breath tests using substrates for different isoenzymes: caffeine (CYP1A2), aminopyrine (CYP2C11), and erythromycin (CYP3A2). Creatinine clearance was reduced by 60% (P <. 01) in rats with CRF. Compared with control paired-fed rats, total CYP450 activity was reduced by 40% in rats with CRF. Protein expression of CYP2C11, CYP3A1, and CYP3A2 was considerably reduced (more than 45%, P <.001) in rats with CRF, whereas the levels of CYP1A2 were unchanged. In rats with CRF, there was a 35% reduction in the aminopyrine (CYP2C11) and the erythromycin (CYP3A2) breath tests compared with control animals (P <.001). The caffeine (CYP1A2) breath tests remained comparable to controls. Creatinine clearance correlated with the aminopyrine and erythromycin breath tests (r(2) = 0.73 and r(2) = 0.81, respectively, P <.001). In conclusion, CRF is associated with a decrease in total liver CYP450 activity in rats (mainly in CYP2C11, CYP3A1, and CYP3A2), which leads to a significant decrease in the metabolism of drugs.
慢性肾衰竭（CRF）与药物经肾排泄减少有关，但其对外源性物质肝脏代谢的影响尚不明确。本研究的目的是确定CRF对肝脏细胞色素P450（CYP450）的影响及其对药物体内肝脏代谢的影响。研究了两组大鼠：对照配对喂养组和CRF组。通过次全肾切除术诱导CRF。在肝微粒体中评估总CYP450活性和几种CYP450同工酶（CYP1A2、CYP2C11、CYP3A1、CYP3A2）的蛋白表达。使用不同同工酶的底物通过呼气试验评估体内细胞色素P450活性：咖啡因（CYP1A2）、氨基比林（CYP2C11）和红霉素（CYP3A2）。CRF大鼠的肌酐清除率降低了60%（P<.01）。与对照配对喂养的大鼠相比，CRF大鼠的总CYP450活性降低了40%。CRF大鼠中CYP2C11、CYP3A1和CYP3A2的蛋白表达显著降低（超过45%，P<.001），而CYP1A2的水平未改变。与对照动物相比，CRF大鼠的氨基比林（CYP2C11）和红霉素（CYP3A2）呼气试验降低了35%（P<.001）。咖啡因（CYP1A2）呼气试验与对照组相当。肌酐清除率与氨基比林和红霉素呼气试验相关（r2分别为0.73和0.81，P<.001）。总之，CRF与大鼠肝脏总CYP450活性降低有关（主要是CYP2C11、CYP3A1和CYP3A2），这导致药物代谢显著降低。
