Decreased acetylation of isoniazid in chronic renal failure

Kim, Yoon-Gu; Shin, Jae‐Gook; Shin, Sang-Goo; Jang, In‐Jin; Kim, Sejoong; Lee, Jung-Sang; Han, Jin-Suk; Cha, Young‐Nam

doi:10.1038/clpt.1993.198

Cited by 63 publications

(47 citation statements)

References 3 publications

(4 reference statements)

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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: 82%

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: 82%

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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“…The reduction CL NR isoniazid was more pronounced in slow acetylators with CRF. Both of these effects were reversed by transplantation [74,75]. These data suggest that with high extraction drugs that also exhibit polymorphic metabolism, poor metabolizers may be at greater risk for adverse effects of CRF on drug metabolism.…”

Section: Clinical Investigations: Effect Of Chronic Renal Failure On mentioning

confidence: 51%

The effect of chronic renal failure on drug metabolism and transport

Dreisbach

Lertora

2008

Expert Opinion on Drug Metabolism & Toxicology

207

154

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Background-Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine.Objectives-The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport.Methods-The National Library of Medicine PubMed was utilized with the search terms 'chronic renal failure, cytochrome P450, liver metabolism, efflux drug transport and uptake transport' including relevant articles back to 1969.Results-Animal studies in CRF have shown a major downregulation (40-85%) of hepatic and intestinal cytochrome P450 (CYP) metabolism. High levels of parathyroid hormone, cytokines, and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein (Pgp) and organic anion transporting polypeptide (OATP) are also affected.Conclusion-CRF alters intestinal, renal, and hepatic drug metabolism and transport producing a clinically significant impact on drug disposition and increasing the risk for adverse drug reactions.

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“…For instance, acetylation of isoniazid is decreased as well as the glucuronidation of morphine, p-aminobenzoic acid, and metoclopramide. [123][124][125][126] Only a few studies have investigated the direct effect of uremic toxins on phase II enzymes. By using primary rat hepatocytes, Simard et al 127 showed that exposure of the cells to clinically relevant concentrations of parathyroid hormone resulted in a reduced gene and protein expression of N-acetyltransferase 2.…”

Section: Intracellular Fate Of Uremic Toxinsmentioning

confidence: 99%

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Masereeuw

Mutsaers

Toyohara³

et al. 2014

Seminars in Nephrology

134

122

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This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited.

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Decreased acetylation of isoniazid in chronic renal failure

Cited by 63 publications

References 3 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

The effect of chronic renal failure on drug metabolism and transport

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

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