Decreased in vivo metabolism of drugs in chronic renal failure

Chronic renal failure (CRF) is associated with a decrease in renal excretio n of drugs, but its effects on the liver metabolism of xenobiotics are poor ly defined. The objectives of this study were to determine the effects of C RF on hepatic cytochrome P450 (CYP450) and its repercussions on in vivo hep atic metabolism of drugs. Two groups of rats were studied: control paired-f ed 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 activit y was evaluated with breath tests using substrates for different isoenzymes : caffeine (CYP1A2), aminopyrine (CYP2C11), and erythromycin (CYP3A2). Crea tinine clearance was reduced by 60% (P < .01) in rats with CRF. Compared wi th control paired-fed rats, total CYP450 activity was reduced by 40% in rat s with CRF. Protein expression of CYP2C11, CYP3A1, and CYP3A2 was considera bly 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 th e aminopyrine (CYP2C11) and the erythromycin (CYP3A2) breath tests compared with control animals (P < .001). The caffeine (CYP1A2) breath tests remain ed comparable to controls. Creatinine clearance correlated with the aminopy rine and erythromycin breath tests (r(2) = 0.73 and r(2) = 0.81, respective ly, P < .001). In conclusion, CRF is associated with a decrease in total li ver CYP450 activity in rats (mainly in CYP2C11, CYP3A1, and CYP3A2), which leads to a significant decrease in the metabolism of drugs.