Several lines of emerging evidence indicate that kidney disease differentially affects uptake and efflux transporters and metabolic enzymes in the liver and gastrointestinal (GI) tract, and uremic toxins have been implicated as the cause. In patients with kidney disease, even drugs that are eliminated by nonrenal transport and metabolism could lead to important unintended consequences if they are administered without dose adjustment for reduced renal function. This is particularly so in the case of drugs with narrow therapeutic windows and may translate into clinically significant variations in exposure and response.

1 Chronic renal failure (CRF) is associated with a decrease in liver cytochrome P450 (P450). The mechanism remains poorly understood. The present study aimed to investigate the e ects of the serum of rats with CRF on liver P450. 2 Normal rat hepatocytes were incubated for 24 h with serum (concentration of 10%) from rats with CRF and from control animals in order to measure (1) total P450 level, (2) protein expression and mRNA levels of major P450 isoforms, and (3) some of their speci®c metabolic activities (Ndemethylation of erythromycin). Time-course experiments (incubation time from 12 to 48 h) and dose-response curves (concentration of serum ranging from 1 to 30%) have been conducted. 3 In normal hepatocytes incubated for 24 h with serum (concentration of 10%) from rats with CRF, total P450 level, protein expression and mRNA levels of several P450 isoforms (CYP2C6, 2C11, 3A1 and 3A2) were decreased by more than 35% (P50.001) compared to serum from control animals. The protein expression as well as the mRNA levels of CYP2D were similar in hepatocytes incubated with serum from either control or CRF rats. The N-demethylation of erythromycin was decreased by more than 35% (P50.001) in hepatocytes incubated with serum from rats with CRF.The inhibitory e ect of serum from rats with CRF tended to peak at 48 h of incubation and was maximum at a concentration of 20%. 4 In conclusion, uremic serum contains mediator(s) that down-regulate the cytochrome P450 of normal hepatocytes secondary to reduced gene expression.

1 In humans, chronic renal failure (CRF) is associated with decreased hepatic drug metabolism, particularly that mediated by the cytochrome P450 (P450). The mechanisms remain poorly understood. The present study aimed to investigate the effects of the serum of patients with CRF on liver P450, and to evaluate whether renal replacement therapies (dialysis or transplantation) impede the inhibition of CRF serum on P450. 2 Rat hepatocytes were incubated for 24 h with serum from patients with severe CRF and from controls to measure (1) P450 level, (2) protein expression and mRNA levels of P450 isoforms and (3) metabolic activities of CYP3A and CYP1A. Similar experiments were performed with serum of patients once on chronic hemodialysis and after kidney transplantation. 3 In rat hepatocytes incubated for 24 h with serum from patients with CRF, P450 level and protein expression, as well as mRNA levels of P450 isoforms (CYP1A2, 2C6, 2C11, 2D1/2D2, 3A2 and 4A1/ 4A3), were decreased by more than 45% (Po0.001) compared to control serum, while the levels of CYP2E1 were not modified. CYP3A and CYP1A activities were decreased by 51 and 59% (Po0.001), respectively. The inhibitory effect of serum obtained from patients before first dialysis was similar after 1 or 6 months on chronic hemodialysis but was lost after successful kidney transplantation. In CRF serum, the fraction containing proteins between 10 and 15 kDa decreases P450. 4 Human uremic serum contains mediator(s) that decreases rat hepatic P450 activity and expression secondary to reduced gene expression. The inhibitory effect of serum persists even after initiation of dialysis, but disappears after normalization of renal function following kidney transplantation.