Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous bumetanide.

The effects of differences in the rate and composition of intravenous (i.v.) fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of bumetanide were evaluated with rabbit as the animal model. Each rabbit received a 4-h constant i.v. infusion of bumetanide at 1 mg/kg with 0% replacement (treatment I, n = 8), 50% replacement (treatment II, n = 6), and 100% replacement (treatment III, n = 7) with lactated Ringer's solution, in addition, another group of rabbits received 100% replacement with 5% dextrose in water (D-5-W, treatment IV, n = 4). Some pharmacokinetic parameters, such as the apparent volume of distribution at steady-state, mean residence time, and terminal half-life, remained relatively unchanged in all four treatments. Renal clearance and urinary excretion rate of the drug in treatments I-III were essentially the same, but were considerably higher than those in treatment IV. In spite of the similarities in kinetic properties (approximately 40% difference between lowest and highest values), the diuretic and/or natriuretic effects of bumetanide were markedly different among the four treatments. For example, the mean 8-h urine output values were 189, 317, 2170, and 306 mL for treatments I-IV, respectively, the corresponding 8-h sodium excretion values were 9.19, 16.5, 88.8, and 15.7 mmol, and the chloride excretion values were 10.8, 33.7, 77.4, and 11.7 mmol. Except for treatment III, diuresis and/or natriuresis were time dependent, generally decreasing with time until reaching a low plateau during later hours of infusion.(ABSTRACT TRUNCATED AT 250 WORDS)