SATURABLE ACCUMULATION AND DIURETIC ACTIVITY OF HYDROCHLOROTHIAZIDE IN THE ISOLATED-PERFUSED RAT-KIDNEY

The role of tubular accumulation in renal disposition and diuretic eff icacy of hydrochlorothiazide was studied in the isolated perfused rat kidney, Hydrochlorothiazide resulted in a dose-dependent increase in t he fractional excretion of sodium, chloride and potassium, and in urin ary flow and pH, Renal clearance of the drug was low as a result of a low extraction ratio and extensive nonionic back-diffusion, Hydrochlor othiazide was subject to saturable tubular secretion, following Michae lis-Menten kinetics, Parameters obtained after nonlinear regression an alysis were a maximum tubular transport velocity of 42 +/- 6 mu g/min, a Michaelis-Menten constant of secretion of 38 +/- 11 mu g/ml and a f raction of excreted drug reabsorbed passively of 0.49 +/- 0.03, The th iazide diuretic accumulated extensively in kidney tissue due to active cellular uptake (maximum capacity of renal accumulation of 500 +/- 27 0 mu g/g; affinity constant of renal accumulation of 28 +/- 16 mu g/ml ) and passive diffusion, Plots were constructed of the sodium excretio n 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 t he 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-resp onse curve indicates that the diuretic effect of hydrochlorothiazide i s restricted by saturable accumulation and secretion.