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

Abstract

The effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of torasemide were evaluated in rabbits. Each rabbit received 2-h constant intravenous infusion of 1 mg kg(-1) torasemide with 0% replacement (treatment 1, n=6), 50% replacement (treatment 2, n=9), 100% replacement with lactated Ringer's solution (treatment 3, n=8), and 100% replacement with 5% dextrose in water (treatment 4, n=6). Total body (4.53, 5.72, 10.0 and 4.45 mL min(-1) kg(-1) for treatments 1-4, respectively) and renal clearance (1.44, 1.87, 6.78 and 1.72 mL min(-1) kg(-1)) of torasemide, and total amount of unchanged torasemide excreted in 8-h urine (A(e 0-8 h): 694, 780, 1310 and 1040 microg) in treatment 3 were considerably faster and greater compared with treatments 1, 2 and 4. Although the difference in A(e 0-8 h) between treatments 1 and 3 was only 88.8%, the diuretic and/or natriuretic effects of torasemide were markedly different among the four treatments. For example, the mean 8-h urine output was 101, 185, 808 and 589 mL for treatments 1-4, respectively, and the corresponding values for sodium excretion were 10.1, 20.6, 89.2 and 29.9 mmol, and for chloride excretion were 14.5, 27.9, 94.0 and 37.2 mmol. Although full fluid replacement was used in both treatments 3 and 4, the 8-h diuretic, natriuretic and chloruretic effects in treatment 3 were significantly greater compared with treatment 4, indicating the importance of the composition of fluid replacement. Both treatments 1 and 4 received no sodium replacement, however, the 8-h diuretic, natriuretic and chloruretic effects were significantly greater in treatment 4 compared with treatment 1, indicating the importance of rate of fluid replacement for the diuretic effects. Therefore, the 8-h diuretic, natriuretic and chloruretic effects were significantly greater in treatment 3 compared with treatments 1, 2 and 4, indicating the importance of full fluid and electrolyte replacement. Some implications for the bioequivalence evaluation of dosage forms of torasemide are discussed.