Saturable Accumulation and Diuretic Activity of Hydrochlorothiazide in the Isolated Perfused Rat Kidney

Masereeuw, Rosalinde; Moons, W. M.; Rüssel, Frans G. M.

doi:10.1159/000139467

Cited by 7 publications

(3 citation statements)

References 13 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: 99%

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: 99%

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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“…Además, el potasio altera el gradiente de voltaje transepitelial, favoreciendo la reabsorción de sodio (14,15). Los datos de diuresis y excreción de electrolitos obtenidos en este estudio con la administración de S. scutellarioides son similares a los reportados con las tiacidas que actúan en el túbulo distal (16).…”

Section: Discussionunclassified

Efecto diurético de la especie Salvia scutellarioides en ratas.

Ramírez¹,

Palacios²,

Gutiérrez³

2006

biomedica

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Introducción. En la medicina tradicional colombiana se usa la infusión de toda la planta llamada "mastranto" u "oreja de perro" (Salvia scutellarioides) por sus efectos antihipertensivos y diuréticos. Hasta ahora no se han hecho estudios experimentales para validar los efectos reportados. Objetivos. Determinar el efecto de S. scutellarioides en la diuresis y concentración de electrolitos urinarios utilizando un modelo en ratas. Materiales y métodos. Veinticuatro ratas Sprague-Dawley machos fueron repartidas al azar en cuatro grupos homogéneos: el grupo 1 recibió solución salina normal; el grupo 2, furosemida (10 mg/kg), y los grupos 3 y 4, S. scutellarioides (1 g/kg y 2 g/kg, respectivamente). Todos los tratamientos se administraron en un volumen de 25 ml/kg de peso del animal. Las ratas se colocaron en una jaula metabólica durante seis horas, y se cuantificó la excreción urinaria y los electrolitos en orina. Resultados. La administración de S. scutellarioides en dosis de 1 y 2 g/kg produjo un aumento significativo de la diuresis comparado con la del grupo control (p<0,01). El efecto diurético se manifestó principalmente a partir de la cuarta hora de administración de S. scutellarioides. La administración de S. scutellarioides en ambas dosis produjo un incremento en la excreción urinaria de potasio y cloro. Conclusiones. El estudio corrobora la aparente actividad diurética de S. scutellarioides reportada por médicos tradicionales, lo que podría explicar su posible efecto antihipertensivo. Se requieren más estudios para determinar el perfil farmacológico y la toxicidad de la planta.Palabras clave: diuréticos, Lamiaceae, Salvia, etnofarmacología, fitoterapia, medicina herbaria. Diuretic effect of an infusion of the herbal plant, Salvia scutellarioides, in rats.Introduction. In the Colombian traditional medicine, an infusion made of the entire plant Salvia scutellarioides (known locally as mastranto or oreja de perro (dog's ear)) is used for its antihypertensive and diuretic effects. However, experimental studies have never been done to validate the reported effects. Objective. In the current study, a rat model was used to determine the effect of S. scutellarioides on rat diuresis and urinary electrolytes concentration. Materials and methods. Twenty-four male Sprague-Dawley rats were distributed in four groups: Group 1-normal saline solution, Group 2-furosemide (10mg/kg), Groups 3 and 4 with S. scutellarioides infusion, 1g/kg and 2g/kg respectively. All treatments were administered in a volume of 25ml/kg of rat weight. After treatment, the rats were placed in a metabolic cage for 6 hours. During this period, urinary excretion was monitored and quantified. At the end of 6 hours, the urinary electrolyte concentrations were measured. Results. The administration of S. scutellarioides at doses of 1 and 2 g/kg produced a significant increase in diuresis when compared to the control group (p<0.01). The administration of S. scutellarioides at these doses also increased the urinary excretion of potassium and chloride. Concl...

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“…Probenecid, a uricosuric agent and a typical inhibitor of organic anion tubular secretion, markedly reduces the renal clearance of anionic diuretics such as furosemide and hydrochlorothiazide. 22,23 The transport of these compounds is further complicated by the observation that the uptake of PAH by OAT1expressing oocytes is reduced in the presence of thiazide diuretics, loop diuretics, and/or carbonic anhydrase inhibitors at clinically relevant concentrations. 24 Thus, these diuretics can out-compete PAH and other anions for transport sites.…”

Section: Drug Interactions With the Organic Anion Systemmentioning

confidence: 99%

Renal Drug Transport and Drug-Drug Interactions

Ronaldson

Bendayan

2002

Journal of Pharmacy Practice

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The kidney plays a vital role in the elimination of xenobiotics including drugs, toxins, and endogenous metabolites. Renal drug elimination involves 3 major processes: glomerular filtration, tubular secretion, and tubular reabsorption. Although glomerular filtration is a simple unidirectional diffusion process, renal tubular secretion and/or reabsorption can involve saturable processes mediated by multiple highly specialized membrane transport systems. Current research has identified that these transport proteins play a significant role in the efficient removal and/or reabsorption of pharmacological agents. Since the majority of membrane transporters have broad substrate specificity, there is a significant risk for drug-drug interactions through competition for similar transport pathways. This article will focus on the cellular expression, localization, and transport properties of various renal drug transport systems (ie, organic anion, organic cation, nucleoside, and adenosine triphosphate [ATP]-dependent efflux transporters). Specific examples of drugs that are transported by each of these mechanisms will be provided. Clinically relevant drug-drug interactions involving renal drug transporters will be discussed to guide the clinician in understanding and preventing these interactions.

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Saturable Accumulation and Diuretic Activity of Hydrochlorothiazide in the Isolated Perfused Rat Kidney

Cited by 7 publications

References 13 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

Efecto diurético de la especie Salvia scutellarioides en ratas.

Renal Drug Transport and Drug-Drug Interactions

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