Hepatic drug metabolism in rats with experimental chronic renal failure

Patterson, Sean E.; Cohn, Victor

doi:10.1016/0006-2952(84)90451-9

Cited by 49 publications

(23 citation statements)

References 27 publications

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“…However, several studies have demonstrated that animals with CRF also exhibit decreased hepatic drug metabolism mediated by cytochrome P450 (5)(6)(7)(8)(9)26,27). Only selected cytochrome P450 isoforms, i.e., CYP2C6, CYP2C11, CYP3A1, and CYP3A2, are decreased in the liver (9,27).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have demonstrated that the metabolic clearance of various substrates is reduced among patients with CRF (1,3,4). Indeed, in rats with experimental renal failure, CRF inhibits liver cytochrome P450, as well as other cytosolic enzymes (5)(6)(7)(8). We recently demonstrated that, in rats, CRF induces marked decreases in liver total cytochrome P450 activity secondary to reduced protein expression of selected cytochrome P450 isoforms, namely CYP2C11, CYP3A1, and CYP3A2 (9).…”

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confidence: 98%

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Downregulation of Intestinal Cytochrome P450 in Chronic Renal Failure

Leblond

Petrucci

Dubé

et al. 2002

Journal of the American Society of Nephrology

152

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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

Downregulation of Intestinal Cytochrome P450 in Chronic Renal Failure

Leblond

Petrucci

Dubé

et al. 2002

Journal of the American Society of Nephrology

152

160

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“…Several animal studies have shown that liver and intestinal P450 are reduced in CRF (7)(8)(9)(10). These studies demonstrated that CRF is associated with a decrease in the activity as well as in the expression of liver and intestinal P450 isoforms secondary to reduced mRNA levels (9,10).…”

mentioning

confidence: 94%

Role of Parathyroid Hormone in the Downregulation of Liver Cytochrome P450 in Chronic Renal Failure

Jl¹,

Naud²,

Chouinard³

et al. 2006

Journal of the American Society of Nephrology

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Chronic renal failure (CRF) is associated with a decrease in drug metabolism secondary to a decrease in liver cytochrome P450 (P450). The predominant theory to explain this decrease is the presence of factors in the blood of uremic patients. This study tested the hypothesis that parathyroid hormone (PTH) could be this factor. The objectives of this study were to determine (1) the role of PTH in the downregulation of hepatocyte P450 induced by rat uremic serum, (2) the role of PTH in the downregulation of liver P450 in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes. For this purpose, (1) hepatocytes were incubated with serum from rat with CRF that was depleted with anti-PTH antibodies or with serum from parathyroidectomized (CRF-PTX) rat with CRF, (2) the effect of PTX on liver P450 was evaluated in rats with CRF, and ( C hronic renal failure (CRF) interferes with the elimination of many drugs because of the reduction in GFR and tubular secretion (1). However, renal failure also diminishes the metabolic clearance of selected drugs secondary to decrease of hepatic and intestinal metabolism of these drugs (2-6). The major determinant for these metabolic changes is a reduction in enzymatic activity.Cytochrome P450 (P450) is the major catalyst of drug biotransformation. Several animal studies have shown that liver and intestinal P450 are reduced in CRF (7-10). These studies demonstrated that CRF is associated with a decrease in the activity as well as in the expression of liver and intestinal P450 isoforms secondary to reduced mRNA levels (9,10). The main hypothesis to explain P450 activity and expression downregulation is the presence in the blood of uremic animals of endogenous inhibitors that modulate the P450. Indeed, we have shown that in normal hepatocytes that were incubated for 24 h with serum from rats with CRF, total P450 level and protein expression of several P450 isoforms decreased by 45% compared with serum from control animals (11). This decrease in protein expression of P450 isoforms was secondary to reduced gene expression (11). Similar results have been shown with serum of patients with severe CRF (12). The next step was to find which factor in the uremic blood downregulates P450 in CRF.CRF is associated with multiple metabolic disturbances. As a consequence, numerous molecules are increased in CRF. However, taking into account the changes that are induced by CRF (metabolic, hormonal, and retention of toxins) and the factors that are known to affect the P450, two main mediators are most likely to be associated with downregulation of P450 in CRF: parathyroid hormone (PTH) and proinflammatory cytokines (6). Although the potency of cytokines to downregulate P450 have been established in inflammatory disease (13), we hypothesized that PTH could be implicated in the downregulation of P450 in CRF for the following reasons: (1) secondary hyperparathyroidism is frequent in CRF (14); (2) PTH is known to downregulate the mRNA of many proteins, particularly in the liver but also in other tiss...

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“…Animal models of acute and chronic renal failure since the late 1960s have shown reduced CYP activity with retained susceptibility to induction [33][34][35][36]. An early ARF study in rats showed increased bioavailability of propranolol, a highly extracted drug [37].…”

Section: Animal Studies: Effect Of Renal Failure On Cyp Metabolismmentioning

confidence: 99%

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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Hepatic drug metabolism in rats with experimental chronic renal failure

Cited by 49 publications

References 27 publications

Downregulation of Intestinal Cytochrome P450 in Chronic Renal Failure

Downregulation of Intestinal Cytochrome P450 in Chronic Renal Failure

Role of Parathyroid Hormone in the Downregulation of Liver Cytochrome P450 in Chronic Renal Failure

The effect of chronic renal failure on drug metabolism and transport

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