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

Abstract

The role of tubular accumulation in renal disposition and diuretic efficacy of hydrochlorothiazide was studied in the isolated perfused rat kidney. Hydrochlorothiazide resulted in a dose-dependent increase in the fractional excretion of sodium, chloride and potassium, and in urinary flow and pH. Renal clearance of the drug was low as a result of a low extraction ratio and extensive nonionic back-diffusion. Hydrochlorothiazide was subject to saturable tubular secretion, following Michaelis-Menten kinetics. Parameters obtained after nonlinear regression analysis were a maximum tubular transport velocity of 42 ± 6 µg/min, a Michaelis-Menten constant of secretion of 38 ± 11 µg/ml and a fraction of excreted drug reabsorbed passively of 0.49 ± 0.03. The thiazide diuretic accumulated extensively in kidney tissue due to active cellular uptake (maximum capacity of renal accumulation of 500 ± 270 µg/g; affinity constant of renal accumulation of 28 ± 16 µg/ml) and passive diffusion. Plots were constructed of the sodium excretion rate versus hydrochlorothiazide perfusate concentration or the renal excretion rate. The perfusate plot could be described by the sigmoid E_max model, while a simplification of the model had to be used for the response curve in urine because a maximum effect was not observed. The apparent maximum effect resulting from the perfusate concentration-response curve and the discrepancy with the renal excretion rate-response curve indicates that the diuretic effect of hydrochlorothiazide is restricted by saturable accumulation and secretion.

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

“…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 ).…”

Efecto diurético de la especie Salvia scutellarioides en ratas.

“…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).…”

Renal Drug Transport and Drug-Drug Interactions

“…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.…”