Pharmacokinetics of cefmenoxime in patients with impaired renal function and in those undergoing hemodialysis

Konishi, Konosuke

doi:10.1128/aac.30.6.901

Cited by 9 publications

(5 citation statements)

References 13 publications

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“…Furthermore, we found a correlation between the dose of mediator(s) (serum concentration) and the decrease in P450 expression (Figure 5). Similar correlation between the decrease in the metabolism of drugs and the levels of renal failure has been described in humans (Konishi, 1986). These results suggest that as CRF worsens, patients are at risk of drug accumulation and toxicity secondary to reduction in their metabolism.…”

Section: Discussionsupporting

confidence: 74%

Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450

Dubé

Naud

et al. 2005

British J Pharmacology

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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.

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Section: Discussionsupporting

confidence: 74%

Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450

Dubé

Naud

et al. 2005

British J Pharmacology

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“…There seems to be a correlation between the decrease in drug metabolism and the severity of renal failure among human subjects (39). Interestingly, in rats, we observed significant correlations of the decrease in renal function with the reduction in intestinal cytochrome P450 levels, as well as with the reductions in cytochrome P450 activity (erythromycin N-demethylation and EROD activities).…”

Section: Discussionsupporting

confidence: 48%

Downregulation of Intestinal Cytochrome P450 in Chronic Renal Failure

Leblond

Petrucci

Dubé

et al. 2002

Journal of the American Society of Nephrology

154

160

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Abstract. Chronic renal failure (CRF) is associated with a decrease in intestinal drug metabolism. The mechanisms remain poorly understood, but one hypothesis involves a reduction in cytochrome P450 levels. This study aimed to investigate the effects of CRF on intestinal cytochrome P450. Two groups of rats were defined, i.e., rats with CRF (induced by 5/6 nephrectomy) and control pair-fed rats. Total cytochrome P450 levels and protein and mRNA expression of cytochrome P450 isoforms, as well as in vitro N-demethylation of erythromycin (a probe for CYP3A activity) and 7-ethoxyresorufin o-deethylase activity (a probe for CYP1A), were assessed in intestinal microsomes. Body weights were similar in the two groups. Creatinine clearance was reduced by 77% (P Ͻ 0.001) in CRF rats, compared with control pair-fed animals. Total intestinal cytochrome P450 activity was reduced by 32% (P Ͻ 0.001) in CRF rats. CYP1A1 and CYP3A2 protein expression was considerably reduced (Ͼ40%, P Ͻ 0.001) in rats with CRF. CYP2B1, CYP2C6, and CYP2C11 levels were the same in the two groups. RT-PCR assays revealed marked downregulation of CYP1A1 and CYP3A2 gene expression in CRF rats (P Ͻ 0.001). Although intestinal cytochrome P450 levels were reduced in CRF, induction by dexamethasone was present. NDemethylation of erythromycin and 7-ethoxyresorufin o-deethylase activity were decreased by 25% (P Ͻ 0.05) in CRF rats, compared with control rats. In conclusion, CRF in rats is associated with decreases in intestinal cytochrome P450 activity (mainly CYP1A1 and CYP3A2) secondary to reduced gene expression.

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“…There seems to be a correlation between the decrease in the metabolism of drugs and the severity of renal failure in human (Konishi, 1986). In the rat, we recently reported in vivo a significant correlation between the decrease in renal function and the reduction in liver cytochrome P450 but also with the reduction in the in vitro N‐demethylation of erythromycin (Leblond et al ., 2000; 2001).…”

Section: Discussionmentioning

confidence: 99%

Down‐regulation of hepatic cytochrome P450 in chronic renal failure: role of uremic mediators

Guévin

Naud

et al. 2002

British J Pharmacology

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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.

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Pharmacokinetics of cefmenoxime in patients with impaired renal function and in those undergoing hemodialysis

Cited by 9 publications

References 13 publications

Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450

Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450

Downregulation of Intestinal Cytochrome P450 in Chronic Renal Failure

Down‐regulation of hepatic cytochrome P450 in chronic renal failure: role of uremic mediators

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