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

Guévin, Carl; Jl, Michaud; Naud, Judith; Leblond, François A.; Pichette, Vincent

doi:10.1038/sj.bjp.0704951

Cited by 94 publications

(87 citation statements)

References 33 publications

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“…As discussed by Sica and Gehr (198), the limited pharmacokinetic studies have not indicated that dosage adjustments of other statins are necessary in renal failure, but the manufacturers have generally recommended lower starting dosages and cautious titration in patients with renal failure. Such recommendations seem prudent given evidence that the state of renal insufficiency has been associated with downregulation of the CYP enzyme system and hepatic metabolism of the drug (201)(202)(203), given the potential alterations in protein binding of these highly proteinbound drugs as a result of uremic toxins, and given the high rate of polypharmacy in this population. As discussed previously, the UK-HARP studies did not indicate higher rates of rhabdomyolysis in patients who had CKD and were treated with simvastatin or ezetimibe/simvastatin (190,192).…”

Section: Safety Of Lld In the Ckd Populationmentioning

confidence: 99%

The Unique Character of Cardiovascular Disease in Chronic Kidney Disease and Its Implications for Treatment with Lipid-Lowering Drugs

Nogueira

Weir

2007

Clinical Journal of the American Society of Nephrology

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D uring the past several decades, the advent and refinement of maintenance dialysis and kidney transplantation have essentially eliminated kidney failure per se as a cause of death in developed countries. However, as patients survive many years after the development of renal failure, comorbidities develop, progress, and ultimately cause death in these individuals. Cardiovascular disease (CVD) has ranked prominent among these comorbidities, accounting for nearly half of the deaths (1). All along the continuum of chronic kidney disease (CKD)-from microalbuminuria to ESRD-a higher risk for CVD has been observed (see Epidemiology of CVD in CKD). In fact, individuals with early CKD are more likely to die of CVD than to develop ESRD (2,3). Then, among those who survive to ESRD, the all-cause CVD mortality in patients with ESRD is many-fold higher than in the general population (4). Unfortunately, the reasons for the association of CKD with CVD are not clearly understood, and the role of various clinical interventions in stemming the CVD epidemic are not well defined. Complicating the issue is the potential variation in the pathophysiology and clinical behavior of CVD through the stages of CKD.3-Hydroxyl-3-methylglutaryl CoA reductase inhibitors (statins) and other lipid-lowering drugs (LLD) have been clearly demonstrated to lessen the morbidity and mortality of CVD in the general population; therefore, there is hope that the use of these drugs may likewise help patients with CKD (In addition, it has been theorized that dyslipidemia may contribute to the progression of CKD, such that LLD may prove to slow CKD progression.) Nevertheless, given differences in epidemiology and pathophysiology of CVD in CKD, there are reasons to question whether the cardiovascular benefits of LLD that are observed in the general population will also be realized in the CKD population. It is widely acknowledged that the current medical literature provides insufficient data to guide the use of LLD in the CKD population, in large part because renal insufficiency has been an exclusion criterion for most of the randomized, controlled studies that have addressed this issue. Although consensus-based guidelines on the treatment of dyslipidemias in individuals with CKD and with kidney transplants have been published by the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) Work Groups, the nephrology and cardiology communities recognize the urgent need for high-quality clinical studies on this issue, and this has fueled the publication of subgroup analyses of previous large studies in the general population and the launching of large-scale clinical trials in the CKD population, as summarized in Table 1. To provide the reader with a better appreciation of the important issues that are germane to management of dyslipidemia in CKD, this article (1) briefly summarizes the literature on the benefits of LLD in the general population, (2) demonstrates the limited involvement of individuals with CKD in the studies in the ge...

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Section: Safety Of Lld In the Ckd Populationmentioning

confidence: 99%

The Unique Character of Cardiovascular Disease in Chronic Kidney Disease and Its Implications for Treatment with Lipid-Lowering Drugs

Nogueira

Weir

2007

Clinical Journal of the American Society of Nephrology

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“…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).…”

mentioning

confidence: 93%

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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“…Studies from the Pichette laboratory demonstrated that the activity and expression of cytochrome P-450 (CYP450) was reduced in the 5/6th nephrectomy (5/6N) rat model of chronic renal failure (6,10,11). Their work elucidated a direct role for uremic solutes with the observation that CYP450 activity and expression were reduced in primary rat hepatocytes incubated with human uremic serum (14).…”

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confidence: 99%

Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

Ryan

Dunn

Decker

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Ryan JC, Dunn KW, Decker BS. Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver. Am J Physiol Regul Integr Comp Physiol 307: R1488 -R1492, 2014. First published October 22, 2014 doi:10.1152/ajpregu.00371.2014.-Clinical studies indicate that hepatic drug transport may be altered in chronic kidney disease (CKD). Uremic solutes associated with CKD have been found to alter the expression and/or activity of hepatocyte transporters in experimental animals and in cultured cells. However, given the complexity and adaptability of hepatic transport, it is not clear whether these changes translate into significant alterations in hepatic transport in vivo. To directly measure the effect of CKD on hepatocyte transport in vivo, we conducted quantitative intravital microscopy of transport of the fluorescent organic anion fluorescein in the livers of rats following 5/6th nephrectomy, an established model of CKD. Our quantitative analysis of fluorescein transport showed that the rate of hepatocyte uptake was reduced by ϳ20% in 5/6th nephrectomized rats, consistent with previous observations of Oatp downregulation. However, the overall rate of transport into bile canaliculi was unaffected, suggesting compensatory changes in Mrp2-mediated secretion. Our study suggests that uremia resulting from 5/6th nephrectomy does not significantly impact the overall hepatic clearance of an Oatp substrate. chronic kidney disease; uremia; cytochrome P-450; hepatic transport; Mrp2; Oatp; sodium fluorescein PATIENTS WITH END-STAGE RENAL disease (ESRD) receiving dialysis take on average 12 medications to manage the complications of their renal failure and their comorbid disease, which places them at a substantial risk for adverse drug events (8,12,13). Currently, modifications in drug dosing to improve safety for ESRD patients have largely been confined to those medications excreted renally. This has likely improved the safety of these medications for the ESRD population, yet it remains an incomplete approach, since it does not include the hepatically metabolized medications. This oversight is significant because evidence increasingly indicates that hepatic drug metabolism and transport are reduced in patients with [14][15][16][17][18][19][20][21][22][25][26][27][28]30). Consequently, administering the full dose of a hepatically metabolized medication may place an ESRD patient at similar risk for an adverse drug event as administering the full dose of a renally eliminated medication.Experimental evidence suggests multiple mechanisms by which uremic solutes might influence hepatic drug disposition (20,25). Studies from the Pichette laboratory demonstrated that the activity and expression of cytochrome P-450 (CYP450) was reduced in the 5/6th nephrectomy (5/6N) rat model of chronic renal failure (6, 10, 11). Their work elucidated a direct role for uremic solutes with the observation that CYP450 activity and expression were reduced in primary rat hepatocytes incubated wit...

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

Cited by 94 publications

References 33 publications

The Unique Character of Cardiovascular Disease in Chronic Kidney Disease and Its Implications for Treatment with Lipid-Lowering Drugs

The Unique Character of Cardiovascular Disease in Chronic Kidney Disease and Its Implications for Treatment with Lipid-Lowering Drugs

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

Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

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