Influence of probenecid and spironolactone on furosemide kinetics and dynamics in man

Abstract

The pharmacokinetics and pharmacodynamics following administration of furosemide (40 mg intravenously) have been studied before and after treatment with probenecid (0.5 gm orally every 6 hr for 3 days) and spironolactone (200-mg initial oral dose followed by 50 mg every 6 hr for 3 days) in 6 normal male subjects. Urine losses during each study period were replaced with saline-dextrose-KCl intravenously. The study was performed with the use of a Latin-square design. Probenecid pretreatment induced significant reductions in renal clearance of furosemide by 78%, the extrarenal clearance by 56%, and the volume of distribution by 52%. As a consequence, furosemide half-life was increased by 54%. Probenecid significantly reduced the rate of sodium excretion at all plasma concentrations of furosemide, but the ratio between urinary furosemide concentration and urinary sodium concentration was not altered. Since the proportion of furosemide excreted unchanged in the urine was not markedly changed, total diuretic response was not influenced by probenecid. There was no evidence of any pharmacokinetic interaction between spironolactone and furosemide. The relationship of furosemide kinetics to dynamics observed in these studies confirms that, in man, the diuretic response is determined by drug that reaches the renal tubule rather than the drug level in plasma.

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

“…For example, coadministration of probenecid decreased the renal clearance and increased elimination half-time and plasma concentrations of intravenously or orally administered furosemide in healthy volunteers (Homeida et al, 1977;Honari et al, 1977;Odlind and Beermann, 1980;Smith et al, 1980;Vree et al, 1995). Another example is the antineoplastic agent methotrexate.…”

Analysis of the natriuretic action of a loop diuretic, piretanide, in man.

“…In order to explain some of the unexpected observations seen by various groups (Branch, 1983;Chennavasin et al, 1979;Dixey et al, 1988;Homeida et al, 1977;Honari et al, 1977), terms such as 'time course of delivery' of drug and the concept of 'maximally efficient dose' have been introduced as important determinants of the overall diuretic response (Kaojarern et al, 1982). Using these terms it was possible to explain why there was a biphasic response, with an initially reduced sodium excretion followed by a subsequent increase; the result was a greater overall natriuretic response to intravenous frusemide, in the presence of probenecid.…”

Probenecid potentiates the hyperglycaemic effect but reduces the diuretic effect of frusemide in mice

“…Since probenecid decreases the clearance and increases the half-life of frusemide in man (Homeida et al, 1977;Honari et al, 1977;Chennavasin et al, 1979) and as the two drugs are quite often given together in clinical practice, the extent to which probenecid affects the diabetogenic action of frusemide in human patients remains to be examined.…”

“…Pretreatment with probenecid abolishes the diuretic response to frusemide in dogs (Hook & Williamson, 1965) and in cats (Friedman & Roch-Ramel, 1977). In humans, pretreatment with probenecid decreases renal and non-renal clearance of frusemide (Homeida et al, 1977;Honari et al, 1977;Chennavasin et al, 1979) with an increase in the plasma concentration and half-life of the drug (Homeida et al, 1977;Honari et al, 1977).…”