Decreased in vivo metabolism of drugs in chronic renal failure.
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.
Leblond
F A
FA
Service de Néphrologie et Centre de Recherche Guy-Bernier, Hopital Maisonneuve-Rosemont, Faculté de Médecine, Université de Montréal, Québec, Canada.
Giroux
L
L
Villeneuve
J P
JP
Pichette
V
V
D000818:Animals; D001944:Breath Tests; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System