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

Abstract

The effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of azosemide were evaluated using rabbit as the animal model. Each rabbit received a 4 h constant intravenous infusion of 1 mg kg−1 azosemide with 0% replacement (treatment I, n =4), 50% replacement (treatment II, n =5), and 100% replacement (treatment III, n =5) with lactated Ringer's solution, as well as with 100% replacement with 5% dextrose in water (D‐5‐W, treatment IV, n =5). Renal clearance and urinary excretion rate of the drug in treatment III were considerably higher than those in treatments I, II, and IV. In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects of azosemide were markedly different among the four treatments. For example, the mean 8 h urine output values were 98·2, 178, 733, and 237 mL for treatments I–IV, respectively, and the corresponding values for sodium excretion were 11·1, 19·4, 76·4, and 14·2 mmol, and for chloride 13·4, 23·8, 78·9, and 17·1 mmol. Except for treatment III, diuresis and/or natriuresis were found to be time dependent, generally decreasing with time until reaching a low plateau during the later hours of infusion. The present findings also show that (i) no fluid replacement and 100% replacement with D‐5‐W both produce the same degree (not significantly different) of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; (ii) in treatment II, where neutral sodium balance was achieved, the development of acute tolerance in diuresis can mainly be attributed to negative water balance under this special condition; and (iii) at steady state the hourly diuresis and natriuresis can differ up to about 6·87‐ and 5·21‐fold between treatments. Some implications for the bioequivalence evaluation of dosage forms of azosemide are discussed. © 1997 John Wiley & Sons, Ltd.

Furosemide Pharmacokinetics and Pharmacodynamics following Gastroretentive Dosage Form Administration to Healthy Volunteers

“…This leads to an increase in electrolyte excretion, 4 which is accompanied by enhanced tubular flow and volume of urine excreted 38 . However, the kinetics of the natriuretic effect and the diuretic effect are not necessarily parallel, as shown in this investigation (see Figure 6) for the studied modes of administration and elsewhere 35 , 36 . It was shown that natriuresis is influenced only to a limited extent by water replacement or total liquid loss 37 .…”

“…Tolerance phenomenon for furosemide was reported before in both animals 25 , 27 , 36 , 37 and humans 32 , 35 . It was related to acute hypovolemia associated with rapid diuresis, which activates compensatory homeostatic mechanisms, leading to increased proximal and distal tubular reabsorption in an effort to preserve an extracellular volume 32 .…”

Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats

“…The pharmacokinetic and pharmacodynamic parameters of i.v. azosemide have been reported to be dependent on the rate and composition of fluid replacement (Park et al, 1997). Therefore, the loss of fluid and electrolytes in urine induced by azosemide was immediately replaced volume-for-volume with lactated Ringer's solution via the jugular vein for up to 8 h after dosing.…”

Pharkacokinetics and pharmacodynamics of furosemide after direct administration into the stomach or duodenum

“…Water and electrolyte losses induced by furosemide were replaced with infusion of equal volume of lactated Ringer's solution via the carotid artery up to 8 h after the dose, because it has been reported that the pharmacodynamics (such as urine output and urinary excretion of sodium) of i.v. furosemide, 15 bumetanide, 16 and azosemide 17 were dependent on the rate and composition of¯uid replacement. The metabolic cage was rinsed with 10 mL distilled water at 8 and 24 h. The rinsings were combined with the urine, and the urinary bladder was cut at 24 h after dosing and washed in the combined 8±24 h urine.…”