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I The pharmacokinetic and diuretic response of frusemide have been investigated in six normal subjects. Frusemide (80 mg) was administered (a) intravenously to unstressed subjects, (b) orally to unstressed subjects, (c) orally to sodium depleted subjects who had received 80 mg oral frusemide 36 h previously followed by a 20 mmol sodium, 160 mmol potassium diet. 2 After i.v. administration, the logarithmic plasma concentration-time curve was biexponential. There was a linear relationship between the frusemide plasma concentration in the 3-phase of elimination and the rate of sodium excretion. Urinary clearance of frusemide was 60% of total plasma clearance, similarly recovery of frusemide in the urine over 36 h was 65% of the dose administered. These observations suggested an extrarenal route of elimination. 3 After oral administration there was also a linear relationship between frusemide plasma concentration and rate of sodium excretion. Oral bioavailability estimated from the ratio of the areas under the plasma concentration-time curve (AUC) and urine recovery over 36 h after i.v. and oral administration was approximately 50%, yet the diuretic response was similar. 4 The AUC of the 1-phase after i.v. administration was similar to the total AUC after oral administration suggesting that response was related to drug present in a tissue pool rather than in plasma. After sodium depletion, there was no change in frusemide kinetics, however the diuretic response decreased. Once again, there was a significant relationship between plasma concentration and rate of sodium excretion. This relationship during the elimination phase after oral administration to sodium depleted subjects was significantly shifted to the right compared to the elimination phase after oral administration to unstressed subjects, suggesting a change in plasma concentration response. 5 In conclusion, the response to frusemide is determined by the concentration of drug in the tissue compartment. This response is modified by factors controlling sodium homeostasis.

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1The pharmacological actions of a new short acting loop diuretic were investigated in nine healthy male subjects and compared with those of frusemide and bumetanide. Subjects received 6 mg piretanide/day, 40 mg frusemide/day or 1 mg bumetanide/day for a period of 1 week.

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.