Effect of chronic renal failure on the expression and function of rat intestinal P‐glycoprotein in drug excretion

Veau, Céline; Leroy, Christine; Banide, Hélène; Auchère, Daniel; Tardivel, Sylviane; Farinotti, Robert; Lacour, Bernard

doi:10.1093/ndt/16.8.1607

Cited by 58 publications

(35 citation statements)

References 25 publications

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“…Veau et al (2001) have demonstrated previously a reduction in the activity of Pgp in CRF rats. However, they did not detect any difference in protein expression of intestinal Pgp in CRF rats.…”

Section: Discussionmentioning

confidence: 77%

“…Pgp function was evaluated by the in vitro transport of Rho-123 (Sigma) across rat everted gut sacs as described previously (Barthe et al, 1999;Veau et al, 2001). The ileum (where Pgp is more abundant) was removed and cut into 6-cm-long segments.…”

Section: Genementioning

confidence: 99%

“…On the other hand, very few studies have described the repercussions of CRF on intestinal drug transporters. Veau et al (2001) reported a decrease in intestinal transport of Rho-123, pointing to an inhibition of intestinal Pgp activity. Furthermore, Huang et al (2000) demonstrated that the incubation of Caco-2 cells with serum from rats with acute renal failure decreases Pgp-mediated transport of Rho-123 (Huang et al, 2000), suggesting that serum from animals with acute renal failure contains mediators that could down-regulate Pgp.…”

mentioning

confidence: 98%

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Down-Regulation of Intestinal Drug Transporters in Chronic Renal Failure in Rats

Naud¹,

Jl²,

Boisvert³

et al. 2006

J Pharmacol Exp Ther

106

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Chronic renal failure (CRF) is associated with an increased bioavailability of drugs by a poorly understood mechanism. One hypothesis is a reduction in the elimination of drugs by the intestine, i.e., drug elimination mediated by protein membrane transporters such as P-glycoprotein (Pgp) and multidrug-resistance-related protein (MRP) 2. The present study aimed to investigate the repercussions of CRF on intestinal transporters involved in drug absorption [organic anion-transportingpolypeptide (Oatp)] and those implicated in drug extrusion (Pgp and MRP2). Pgp, MRP2, MRP3, Oatp2, and Oatp3 protein expression and Pgp, MRP2, and Oatp3 mRNA expression were assessed in the intestine of CRF (induced by five-sixth nephrectomy) and control rats. Pgp and MRP2 activities were measured using the everted gut technique. Rat enterocytes and Caco-2 cells were incubated with sera from control and CRF rats to characterize the mechanism of transporters' down-regulation. Protein expression of Pgp, MRP2, and MRP3 were reduced by more than 40% (p Ͻ 0.01) in CRF rats, whereas Oatp2 and Oatp3 expression remained unchanged. There was no difference in the mRNA levels assessed by real-time polymerase chain reaction. Pgp and MRP2 activities were decreased by 30 and 25%, respectively, in CRF rats compared with control (p Ͻ 0.05). Uremic sera induced a reduction in protein expression and in activity of drug transporters compared with control sera. Our results demonstrate that CRF in rats is associated with a decrease in intestinal Pgp and MRP2 protein expression and function secondarily to serum uremic factors. This reduction could explain the increased bioavailability of drugs in CRF.

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Section: Discussionmentioning

confidence: 77%

Section: Genementioning

confidence: 99%

mentioning

confidence: 98%

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Down-Regulation of Intestinal Drug Transporters in Chronic Renal Failure in Rats

Naud¹,

Jl²,

Boisvert³

et al. 2006

J Pharmacol Exp Ther

106

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“…Also, P-glycoprotein transporter is an energy-dependent multidrug efflux pump that serves to protect against toxic compound accumulation by transporting such substances, which include statins, into the intestinal lumen, bile, and urine. Cyclosporine but not tacrolimus has been shown to be a potent inhibitor of P-glycoprotein (213,214), and its transport activity seems to be reduced in rats with chronic renal failure (215). Clearly, this inhibition of hepatic uptake and enteric efflux of statins in cyclosporine-treated patients could increase risk for toxic accumulation.…”

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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“…The transport of Rh-123, vinblastine, FD-4, and the rhizoma coptidis alkaloids across rat everted sacs was evaluated as described (Veau et al, 2001), with modifications. In brief, 12 rats were used in each everted gut sac experiment.…”

Section: Lc/ms/ms Analysis Of Rhizoma Coptidis Alkaloidsmentioning

confidence: 99%

Increased Systemic Exposure to Rhizoma Coptidis Alkaloids in Lipopolysaccharide-Pretreated Rats Attributable to Enhanced Intestinal Absorption

Ma¹,

Yao²,

Zhong³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Rhizoma coptidis is a rhizome commonly used in traditional Chinese medicine. After oral administration of rhizoma coptidis extract, the plasma concentrations of its effective alkaloid constituents are so low that their systemic therapeutic actions cannot be explained. This study aimed to investigate the influence of lipopolysaccharide (LPS) on the pharmacokinetics of the rhizoma coptidis alkaloids. Pharmacokinetic experiments were performed with rats; both in vitro absorption and efflux experiments were carried out with everted rat gut sacs, whereas in vitro metabolism experiments were conducted with rat liver microsomes and intestinal S9 fractions. Mucosal changes were evaluated with light microscopy and transmission electron microscopy. The results showed that, in rat plasma, LPS pretreatment increased systemic alkaloid exposure. LPS pretreatment increased the in vitro absorption of the alkaloids and decreased their efflux. The efflux of vinblastine and rhodamine 123, P-glycoprotein substrates, also was decreased. The absorption of fluorescein isothiocyanate-labeled dextran (average molecular mass, 4 kDa), a gut paracellular permeability probe, was not influenced. Obvious damage was observed in the mucosa, but the tight junctions between epithelial cells remained intact. Intestinal, rather than hepatic, alkaloid metabolism was decreased. These findings indicated that LPS pretreatment increased systemic exposure to the alkaloids through enhancement of their absorption, which was related to decreased intestinal efflux and metabolism. The results add to the understanding of why rhizoma coptidis is active despite the low plasma concentrations of the rhizoma coptidis alkaloids measured in normal subjects and experimental animals.

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Effect of chronic renal failure on the expression and function of rat intestinal P‐glycoprotein in drug excretion

Abstract: Intestinal secretion of rhodamine 123 is mainly mediated by P-glycoprotein. It was reduced in rats with chronic renal failure, reflecting reduced intestinal drug elimination via a decrease in P-glycoprotein transport activity rather than via protein underexpression.

Cited by 58 publications

References 25 publications

Down-Regulation of Intestinal Drug Transporters in Chronic Renal Failure in Rats

Down-Regulation of Intestinal Drug Transporters in Chronic Renal Failure in Rats

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

Increased Systemic Exposure to Rhizoma Coptidis Alkaloids in Lipopolysaccharide-Pretreated Rats Attributable to Enhanced Intestinal Absorption

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