Effect of probenecid on the dose-response relationship of bumetanide at steady state

The present investigation was undertaken to clarify the determinants of the pharmacologic responses to bumetanide. The urinary excretion rate, plasma concentration and natriuretic and diuretic effects of bumetanide were evaluated under steady-state conditions in four mongrel dogs, before (Treatment I) and after (Treatment II) probenecid administration. To avoid fluid and electrolyte imbalance, urinary losses were replaced i.v. by equal volumes of lactated Ringer's solution over the time interval of the subsequent collection period. Probenecid administration caused a dramatic reduction in the renal clearance of bumetanide (5.05 +/- 1.11 for Treatment I vs. 0.716 +/- 0.285 ml/min . kg for Treatment II; P less than .002), resulting in significantly higher plasma concentrations (3-fold) and significantly lower urinary excretion rates (2.5-fold) of the diuretic. This was accompanied by concomitant reductions in bumetanide-induced diuresis and natriuresis. The results from this study demonstrate that adequate luminal levels of bumetanide are required for the pharmacodynamics of the drug.