ANALYSIS OF THE NATRIURETIC ACTION OF A LOOP DIURETIC, PIRETANIDE, IN MAN

1 The renal responses to a loop diuretic, piretanide, were investigated in a group of fourteen healthy volunteers. The effect of fluid replacement on the drug-response relationship was evaluated in the absence and in the presence of probenecid pretreatment following both oral and intravenous administration of piretanide. 2 Urinary excretion of piretanide was greater when volume losses were replaced than in the absence of volume replacement (i.v. dose: 3.32 +/- 0.15 vs 2.55 +/- 0.23 mg 6 h-1, P < 0.01; oral dose: 2.57 +/- 0.09 vs 1.87 +/- 0.27 mg 6 h-1, P < 0.01). With intravenous piretanide urinary excretion of sodium was likewise greater in the fluid replaced group (198 +/- 4 vs 141 +/- 10 mmol 6 h-1, P < 0.01); these differences caused by fluid replacement did not however occur after oral dosing of piretanide (181 +/- 12 vs 167 +/- 14 mmol 6 h-1). 3 Probenecid pretreatment significantly decreased the renal excretion of piretanide in all subjects and consistently decreased the natriuretic response with the exception of intravenous piretanide challenge in subjects not undergoing fluid replacement. In this situation, despite probenecid causing a decrease in the amount of drug excreted (2.55 +/- 0.23 vs 1.63 +/- 0.15 mg 6 h-1, P < 0.05) the sodium output was unaltered (141 +/- 10 vs 152 +/- 16 mmol 6 h-1, NS). 4 Complete replacement of the induced fluid losses resulted in the enhancement of the renal response, without affecting the shape of the diuretic response curve, of either the intravenous or orally administered piretanide. The natriuretic-response curve of intravenous piretanide alone was observed to be displaced to the right of that seen after oral administration. This implies a fundamental difference in pharmacokinetic-pharmacodynamic relationship of piretanide for the two routes of administration. Pretreatment with probenecid eliminated the observed differences in the drug-response curves, between intravenous and orally administered piretanide, such that the curves were now superimposable irrespective of the route of administration of the diuretic. 5 The differences between the drug-response curves of intravenous and orally administered piretanide shows that a substantial portion of drug delivered to the kidney, after intravenous dosing was wasted as it failed to participate in the pharmacological response. Probenecid prevented this 'wastage' and altered the profile of the drug-response relationship of intravenously administered diuretic. This suggests that caution is needed in interpreting the renal pharmacodynamic responses elicited when bolus doses of diuretics have been administered intravenously.