Metabolism of procainamide in patients with chronic heart failure, chronic respiratory failure and chronic renal failure

Souich, P. du; Erill, S.

doi:10.1007/bf00560254

Cited by 27 publications

(16 citation statements)

References 20 publications

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“…Previous studies have shown that CRF was associated with a decrease in acetylation of drugs, implying that phase II enzymes could also be modified in CRF (du Souich and Erill, 1978;Kim et al, 1993). The results of the present study clearly support this hypothesis because we found a decrease in NAT2 expression in CRF animals.…”

Section: Discussionsupporting

confidence: 90%

Down-Regulation of Liver Drug-Metabolizing Enzymes in a Murine Model of Chronic Renal Failure

Dani¹,

Boisvert²,

Jl³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Drug metabolism could be altered in patients with chronic renal failure (CRF). In rats, this phenomenon is related to a decrease in liver cytochrome P450 (P450) and phase II enzymes, particularly N-acetyltransferase 2 (NAT2). This study attempted to determine the effects of CRF on liver P450 isoforms and NAT2 expressions by using a CRF mouse model. Two groups of mice were studied: CRF induced by 3/4 nephrectomy and control. Liver protein expression and mRNA levels of the major P450 isoforms involved in drug metabolism (CYP1A2, 2C29, 2D, 2E1, and 3A11) and NAT2 were measured by Western blot and realtime polymerase chain reaction (PCR), respectively. CYP3A activity was also assessed by the N-demethylation of erythromycin. Results showed a significant reduction in the protein expression of CYP1A2 (56%), 2C29 (31%), and 3A11 (37%) in CRF mice compared with control animals. Real-time PCR revealed a similar reduction in mRNA levels of CYP1A2, 2C29, and 3A11 (59, 56, and 37%, respectively), in CRF mice. There was no significant modification in protein expression and mRNA of CYP2D and 2E1. Compared with control animals, CRF mice displayed a 25% reduction in N-demethylation of erythromycin. For NAT2, protein expression decreased by 33% and mRNA levels decreased by 23%. In conclusion, this study demonstrates that protein expression of liver CYP1A2, CYP2C29, and CYP3A11 is down-regulated in CRF mice, secondary to reduced gene expression. Phase II enzymes are similarly affected by CRF. Our results will allow the use of knockout mice to determine the mechanism underlying CRF-induced down-regulation of liver drug-metabolizing enzymes.

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Section: Discussionsupporting

confidence: 90%

Down-Regulation of Liver Drug-Metabolizing Enzymes in a Murine Model of Chronic Renal Failure

Dani¹,

Boisvert²,

Jl³

et al. 2009

Drug Metab Dispos

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“…This was clinically important since etomidate and succinylcholine are likely to be used simulta neously in anesthetic procedures and since it has been shown that plasma esterase activity is depressed in some diseases. Thus, it has been reported that the half-life of procaine, used as an indicator of plasma esterase activity, is depressed in patients with renal failure, chronic liver disease or chronic respiratory insufficiency (2,3,13). The results presented here, about procaine half-life in plasma from normal volun teers and from patients with renal failure or chronic liver disease, closely correspond with results previously reported in the literature (2,13).…”

Section: Discussionsupporting

confidence: 81%

Etomidate and Plasma Esterase Activity in Man and Experimental Animals

Calvo¹,

Carlos²,

Erill³

1979

Pharmacology

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No hydrolysis of etomidate in plasma in vitro was detected in samples from man, horse, cow, sheep, guinea pig or white rabbit. Brown rabbits showed a moderate degree of hydrolysis and it was marked in plasma from Wistar rats. In this species, a single enzyme, an aliesterase, participated in the hydrolysis in plasma. Etomidate did not interfere with the hydrolysis of procaine by plasma pseudocholinesterase in man.

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“…20,31,32 Acetylation also seems to be reduced in patients with CRF; several reports have demonstrated that the metabolic clearance of procainamide is reduced by approximately 60% in renal failure. 2,23,24 Moreover, a decrease in the acetylation of isoniazid has been reported in patients with CRF. 22 The mechanism leading to a decrease in phase II enzymatic reactions in CRF is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…6 -9 For instance, zidovudine and morphine (two glucuronidated molecules) have a significantly reduced metabolic clearance in CRF. 20,21 Moreover, several drugs extensively acetylated (e.g., isoniazid, procainamide) also accumulate in patients with decreased renal function, 2,[22][23][24] suggesting a reduction in hepatic acetylation. Recently, Yu et al 25 showed that liver UGT was unchanged in a CRF rat model; however, no study has been done on the effect of CRF on hepatic acetylation in rat.…”

mentioning

confidence: 99%

Downregulation of Hepatic Acetylation of Drugs in Chronic Renal Failure

Simard¹,

Naud²,

Jl³

et al. 2008

Journal of the American Society of Nephrology

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Drug metabolism can be affected by chronic renal failure (CRF). Although it is known that several drugs that are known to be acetylated accumulate in CRF, the effect of CRF on N-acetyltransferase (NAT), the enzyme responsible for this acetylation, is unknown. Herein is reported that protein and gene expression of both Nat isoforms in the liver was reduced by Ͼ30% and Nat2 activity was reduced by 50% in rats with CRF compared with control rats. Incubation of hepatocytes with serum from rats with CRF suggested that a circulating factor is responsible for the decrease in protein and gene expression. For testing the hypothesis that parathyroid hormone may be this factor, CRF was induced in parathyroidectomized rats; downregulation of Nat expression and activity was not observed in these rats. Furthermore, addition of parathyroid hormone to cultured hepatocytes induced a decrease in Nat2 protein and gene expression. In conclusion, liver acetylation of drugs in a rat model of CRF is reduced by a downregulation of Nat1 and Nat2 isoforms, secondary to decreased gene expression. Parathyroid hormone seems to be an important mediator of this phenomenon.

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Metabolism of procainamide in patients with chronic heart failure, chronic respiratory failure and chronic renal failure

Cited by 27 publications

References 20 publications

Down-Regulation of Liver Drug-Metabolizing Enzymes in a Murine Model of Chronic Renal Failure

Down-Regulation of Liver Drug-Metabolizing Enzymes in a Murine Model of Chronic Renal Failure

Etomidate and Plasma Esterase Activity in Man and Experimental Animals

Downregulation of Hepatic Acetylation of Drugs in Chronic Renal Failure

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