Renal Handling and Effects of Salicylic Acid in the Isolated Perfused Rat Kidney

Cox, P. Gerard; Moons, W. M.; Rüssel, Frans G. M.; Ginneken, C. A. M. Van

doi:10.1111/j.1600-0773.1991.tb01247.x

Cited by 9 publications

(5 citation statements)

References 16 publications

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“…However, as shown in Table 2, several organic anion uptake transporters may account for high intracellular concentrations in renal proximal tubule. We showed previously up to 20‐fold accumulation of salicyluric acid and hydrochlorothiazide in rat kidney ( Cox et al ., 1989 ; Masereeuw et al ., 1997 ), indicating that local proximal tubular concentrations may reach even higher levels. Furthermore, studies in Mrp4 knockout mice have shown that Mrp4 accounts for the luminal efflux of furosemide and hydrochlorothiazide at therapeutic plasma concentrations ( Hasegawa et al ., 2007 ).…”

Section: Discussionmentioning

confidence: 90%

Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4

El-Sheikh

Heuvel

Koenderink

et al. 2008

British J Pharmacology

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Background and purpose: The xanthine oxidase inhibitors allopurinol and oxypurinol are used to treat hyperuricaemia, whereas loop and thiazide diuretics can cause iatrogenic hyperuricaemia. Some uricosuric drugs and salicylate have a bimodal action on urate renal excretion. The mechanisms of action of these hypo-and hyperuricaemic drugs on the handling of urate in renal tubules have not been fully elucidated. Recently, we identified the multidrug resistance protein (MRP) 4 as a luminal efflux transporter for urate in the proximal tubule. Experimental approach: Here, we studied the effect of these drugs on [ 14 C]urate transport using human embryonic kidney 293 cells overexpressing human MRP4 and in membrane vesicles isolated from these cells. Key results: Allopurinol stimulated MRP4-mediated cellular urate efflux and allopurinol and oxypurinol both markedly stimulated urate transport by MRP4 in membrane vesicles. Bumetanide and torasemide had no effect, whereas furosemide, chlorothiazide, hydrochlorothiazide, salicylate, benzbromarone and sulfinpyrazone inhibited urate transport, at concentrations ranging from nanomolar up to millimolar. Probenecid stimulated urate transport at 0.1 mM and inhibited transport at higher concentrations. Conclusions and implications: These data suggest that inhibition of MRP4-mediated urate efflux by furosemide and thiazide diuretics could have an important function in their hyperuricaemic mechanisms. Furthermore, stimulation of MRP4-mediated renal urate efflux could be a new mechanism in the hypouricaemic action of allopurinol and oxypurinol. In conclusion, MRP4 may provide a potential target for drugs affecting urate homoeostasis, which needs to be further evaluated in vivo.

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Section: Discussionmentioning

confidence: 90%

Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4

El-Sheikh

Heuvel

Koenderink

et al. 2008

British J Pharmacology

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“…However, the major metabolite of phenacetin is acetaminophen, which accumulates within the papillae (95). Accumulation of NSAIDs in animal renal tissue has been demonstrated for a variety of NSAIDs, but studies do not specify whether there were differences among tissue compartments such as the papillae (21)(22)(23).…”

Section: Analgesic-associated Nephropathymentioning

confidence: 97%

Renal Toxicity of the Nonsteroidal Anti-Inflammatory Drugs

Murray¹,

Brater²

1993

Annu. Rev. Pharmacol. Toxicol.

272

150

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NSAIDs pose little threat of renal insult in normal, healthy persons at therapeutic dosages. However, NSAID administration to susceptible persons may cause decrements in renal plasma flow and glomerular filtration rate within hours. Such acute noxious renal effects are mediated by products of arachidonic acid metabolism. Precipitous decrements in glomerular filtration and renal ischemia, manifested by increased serum creatinine and urea nitrogen, are possible. However, these effects are usually fully reversible with prompt discontinuation of the offending NSAID. Risk factors for the development of these acute renal effects are known. Acute interstitial nephritis with or without nephrotic syndrome is a rare form of renal toxicity that typically occurs between 2-18 months of use. Renal impairment may be so severe as to require temporary hemodialysis; however, renal function usually returns to normal upon discontinuation of the NSAID. The mechanism of acute interstitial nephritis is presumed to be of allergic origin but could also be caused by a reactive metabolite. Fenoprofen use appears to be associated with a much higher risk for its development. In contrast to the acute effects of NSAIDs, irreversible, analgesic-associated nephropathy manifested by papillary necrosis and chronic interstitial nephritis may occur following months to years of high doses of analgesic mixtures. The mechanism by which combination analgesics produce this form of renal injury is unknown and could be either a result of medullary ischemia or a direct effect of a reactive metabolite. An important issue to be resolved is the relationship between the acute, reversible, prostaglandin-mediated renal effects of the NSAIDs and chronic, irreversible destruction, if such a relationship exists. Theoretically, continual or repeated decrements in renal function in patients with predisposing risk factors could cause or contribute to progressive deterioration in renal function. Elevations in blood pressure or interference with the effects of antihypertensive medications could theoretically also contribute to long-term renal deterioration. In addition to renal syndromes caused by NSAIDs that result in renal impairment, other transient effects on electrolyte and water metabolism may also occur. Reduced secretion of sodium may result in formation of edema, exacerbation of heart failure, or increased blood pressure. Hyporeninemic-hypoaldosteronism may produce hyperkalemia. Finally, reduced excretion of water has rarely caused hyponatremia. It has been suggested that NSAIDs may be renoprotective in patients with nephrotic syndrome. Others have suggested that sulindac is "renal-sparing" because of a unique metabolic pathway that supposedly limits the exposure of the kidney to the active sulfide metabolite.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…We have previously shown that the isolated perfused rat kidney is a useful means of investigation of renal secretion and accumulation of drugs (Cox et al 1989(Cox et al , 1990Boom et al 1994). An advantage of this technique is that it enables accurate determination of renal drug clearance over a wide concentration range, under controlled protein-binding conditions and in the absence of non-renal effects.…”

mentioning

confidence: 99%

Renal Excretion and Accumulation Kinetics of 2-Methylbenzoylglycine in the Isolated Perfused Rat Kidney

Masereeuw

Moons

Rüssel

1996

Journal of Pharmacy and Pharmacology

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The effect of protein binding on kidney function has been studied by investigating the renal accumulation and secretion of the hippurate analogue 2-methylbenzoylglycine in the isolated perfused rat kidney in the absence and presence of bovine serum albumin (BSA), Experiments were performed with either 2-5% pluronic or a combination of 2-2% pluronic and 2% BSA as oncotic agents; a wide concentration range (1-190 fig inL~1) of 2-methylbenzoylglycine was studied. Tubular secretion appeared to be a function of the amount of unbound drug in the perfusate and was best described by a model consisting of a high and low affinity Michaelis-Menten term. Parameters obtained after the analysis^of renal excretion data were maximum transport velocity for the high affinity site (TM iH ) -3 -0 db 2-8 fig min" , Michaelis-Menten constant for tubular transport for the high affinity site (KTfH ) = 0-5 ± 0-8 fig mL , maximum transport velocity for the low affinity site ^, 0 -2503:36 ¿¿g_min~ , and Michaelis-Menten constant for tubular transport for the low affinity site ( K T(l ) = 62 ±17 fig mL-1 . The compound accumulated extensively in kidney tissue, ratios up to 175 times the perfusate concentration were reached. Accumulation data were best analysed by a two-site model similar to the model used to describe renal excretion. Calculated parameters were theoretical maximum capacity of the high affinity site (Rm,h) = 26 ± 23 f i g g~\ affinity constant for renal accumulation at the high affinity site (KaiH ) = 0*2±04 ¿¿gmL" 1, theoretical maximum capacity of the low affinity site (RM<) = 1640± 1100 jug g and affinity constant for renal accumulation at the low affinity site (K a ,l) = 60± 58 fig mL-1 .TThe very high accumulation in kidney tissue could be explained by active tubular uptake, mediated by the secretory mechanisms involved, and dependent on the amount of free drug in the perfusate. This study shows that anionic drugs, subject to active secretion, may reach high concentrations in tubular cells even at low plasma concentrations.

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Renal Handling and Effects of Salicylic Acid in the Isolated Perfused Rat Kidney

Cited by 9 publications

References 16 publications

Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4

Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4

Renal Toxicity of the Nonsteroidal Anti-Inflammatory Drugs

Renal Excretion and Accumulation Kinetics of 2-Methylbenzoylglycine in the Isolated Perfused Rat Kidney

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