Combination of long-acting furosemide and instant-acting amiloride: pharmacokinetics and pharmacodynamics in human subjects

Summary— The pharmacokinetics and pharmacodynamics of the combination of amiloride (2 times 2.5 mg) and long-acting furosemide (2 times 10 mg) were compared with amiloride (5 mg) and furosemide (20 mg) in 12 healthy male volunteers aged 26.2 ± 1.6 years and weighing 68.8 ± 6.2 kg, after random order administration. Furosemide and amiloride plasma or urine concentrations were determined by HPLC with fluorimetric detection. The rate of absorption ( t _max = 3 h) and the bioavailability of the two diuretics were not significantly modified by their combination. Furosemide plasma half-life was 2.77 ± 1.04 h after the combination treatment and 2.76 ± 0.98 h alone, amiloride plasma half-life was respectively 15.7 ± 4.6 h and 14.6 ± 3.7 h. The urinary elimination of furosemide was significantly higher in the 2–4 h interval in the combination treatment, accompanying its delayed maximum effect of diuresis. A synergistic effect was observed after the combination administration of the two diuretics; between the 2nd and the 8th hour, the sodium elimination was significantly increased ( P < 0.01) and the potassium excretion was significantly decreased ( P = 0.05). After a single dose, no modification of plasma or erythrocyte magnesium levels was observed. This study shows that the combination of the two drugs entails a synergy of their activities which does not involve pharmacokinetic changes.