FRUSEMIDE AND ITS ACYL GLUCURONIDE SHOW A SHORT AND LONG PHASE IN ELIMINATION KINETICS AND PHARMACODYNAMIC EFFECT IN MAN

The pharmacokinetics of 80 mg frusemide given orally were investigated in normal subjects using a direct HPLC method for parent drug and its acyl glucuronide conjugate. Two half-lives could be distinguished in the plasma elimination of both frusemide and its conjugate with values of 1.25+/-0.75 and 30.4+/-11.5 h for frusemide and 1.31+/-0.60 and 33 .2+/-28.0 h for the conjugate. The renal excretion rate-time profile s howed two phases; the rapid elimination phase lasted from 0-15 h and t he second and slow phase, from 15-96 h. During the first 15 h, 33.3+/- 4.8% of the dosed frusemide was excreted; in the remaining period 15-9 6 h, 4.6+/-1.5% was excreted. In the same two periods the excretion of the glucuronide was 13.4+/-4.7 and 1.9+/-1.1%, respectively. The mean renal clearance of frusemide was 90.2+/-16.9 mL min(-1) during the fi rst period and 91.5+/-29.3 mL min(-1) in the remaining period, during which the stimulation of urine production was absent. The renal cleara nce of the acyl glucuronide was 702+/-221 mL min(-1) in the first peri od, but only 109+/-51.0 mL min(-1) in the second period, The stimulate d urine production in the first 6 h after administration amounted to 2 260+/-755 mL (measured urine production minus baseline value of 1 mL m in(-1) (360 mL). During the second or rebound period (6-96 h after dru g administration), the quantity of urine was 990+/-294 mt lower than w hat would have been expected from the baseline production of 5400 mL. This reduced production (0.82 mL min(-1)) is equivalent to an 18% redu ction in the average urine flow rate of 1 mL min(-1).