PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF PIRETANIDE IN RABBITS. I. EFFECT OF DIFFERENT HYDRATED CONDITIONS

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The pharmacokinetics and pharmacodynamics of piretanide in rabbits were investigated. After intravenous administration, the plasma concentrations and the urinary excretion rates of piretanide, as well as the pharmacologic effects, were measured under two different hydrated conditions. In one experiment, the amount of the body fluid which was lost during diuresis was replaced by infusing Ringer's solution at exactly the same rate with the urine flow rate (treatment I). In another experiment, no compensatory infusion was made (treatment II). There was no appreciable difference between treatment I and II, as far as the plasma concentrations and urinary excretion rate were concerned. In spite of the similarities in the pharmacokinetic properties, the pharmacologic effects of piretanide were influenced considerably by the hydrated conditions of the body. The diuretic effect expressed as the excretion rate of the sum of urinary sodium and potassium was plotted against the corresponding urinary excretion rate of unchanged piretanide. The shape of the each graph showed a similar sigmoid like curve ; however, the curve in treatment I was significantly shifted to the right compared to that in treatment II. This fact indicated that the pharmacologic effect of piretanide seemed to be modified by the contents of water and electrolytes in the body. The plasma concentrations and urinary excretion of piretanide were reasonably described by a linear three compartment open model. Although the diuretic effect of piretanide was related to the hypothetical biophase compartment using the conventional Hill's equation, the difference of pharmacologic intensity between the treatments could not be explained. Then, we introduced a feedback mechanism representing the depletion of body fluid into the Hill's equation and applied this equation to the pharmacologic response of piretanide. The results indicated that the diuretic effects of piretanide in treatment II (in the progressive hydropenic state) as well as in treatment I (in the hydrated state) were well explained.
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PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF PIRETANIDE IN RABBITS. I. EFFECT OF DIFFERENT HYDRATED CONDITIONS

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