Muzolimine: Renal site of action and interaction with probenecid in humans

Muzolimine (60 mg, administered orally) was administered to eight healthy volunteers, under conditions of altered fluid load, to elucidate its renal site of action. The duration of action and the effect of probenecid pretreatment on muzolimine response was also investigated. Muzolimine had a rapid onset of action, with the diuresis complete within 4 hours after dosing. At peak natriuresis, under hydrated conditions, fractional excretion of free water remained unaltered (9.72% ± 0.59% versus 9.07% ± 0.44%; difference not significant) but was accompanied by a significant increase in the delivery of sodium out of the proximal tubule, as measured by fractional excretion of lithium (22% ± 2% to 31% ± 1%; p < 0.01). The fraction of sodium reabsorbed in the distal tubule also decreased from 94% ± 1% to 67% ± 1% ( p < 0.001) of the delivered load. The fractional reabsorption of free water during hydrope‐nia decreased after muzolimine (5.63% ± 0.26% to 2.00% ± 0.81%; p < 0.05). Pretreatment with probenecid resulted in a prominent decrease in urinary sodium excretion (246 ± 25 mmol/24 hr for muzolimine alone; 161 ± 24 mmol/24 hr for muzolimine and probenecid; p < 0.01). These findings suggest that muzolimine has a major site of action in the medullary portion of the thick ascending limb of Henle with additional inhibitory activity on the proximal tubule. It is likely that the active secretion of one or more of the acidic metabolites of muzolimine, by way of the probenecid sensitive organic acid pathway, is responsible for mediating the renal actions this basic drug. Clinical Pharmacology and Therapeutics (1991) 50, 564–572; doi: 10.1038/clpt.1991.182