Clinical Pharmacokinetics of Some Newer Diuretics

Abstract

Several new diuretics have recently been developed. This review summarises the published knowledge about some of them. Azosemide is a loop diuretic. The bioavailability is about 15% and it has a half-life of 2 to 3 hours. Renal and non-renal clearance are 1.32 and 5.4 L/h, respectively. Etozolin is also a loop diuretic. It is rapidly metabolised to the active metabolite, ozolinone. The gastrointestinal uptake of etozolin is almost complete. The plasma half-life of etozolin and ozolinone are 2 and 10 hours, respectively. The compounds are mainly eliminated as metabolites. Renal and liver impairment do not seem to change the pharmacokinetics. Fenquizone has properties similar to the thiazides. The plasma half-life is approximately 17 hours. Apparent volume of distribution averaged 686 L and renal clearance is 7.2 L/h. Indapamide acts predominantly on the proximal segment of the distal tubule and also has direct vasodilatory effects. Gastrointestinal uptake is at least 80%. The drug binds highly to carbonic anhydrases of red blood cells. Protein binding is about 80%, while terminal plasma half-life is 15 hours and the apparent volume of distribution 25 L. Renal clearance is 0.3 L/h and non-renal clearance 0.9 L/h. Several metabolites have been described, of which one major metabolite is pharmacologically active. Muzolimine is a loop diuretic. Its uptake is almost complete, but decreased substantially by food. The protein binding is about 65%, the apparent volume of distribution is about 1 L/kg and average terminal half-life 10 to 20 hours. Elimination is mainly non-renal, and non-renal clearance ranges between 0.5 and 1.32 L/h. The pharmacokinetics of the drug do not seem to be changed in cardiac failure. Terminal plasma half-life is essentially unchanged in patients with renal failure, except in those with very severe reduction of glomerular filtration rate. Piretanide is a loop diuretic which is about 6 times as potent as frusemide (furosemide). Its bioavailability is most likely complete in healthy subjects and in renal patients. Protein binding in healthy subjects is about 95%. The plasma half-life of the drug is about 1 hour and apparent volume of distribution averages about 17 L. Renal and non-renal clearance are about 6 L/h, although renal clearance is decreased in renal failure: this decrease is correlated with glomerular filtration rate. Non-renal clearance is unchanged in renal failure, as is the apparent volume of distribution.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetic and pharmacodynamic changes of azosemide after intravenous and oral administration of azosemide to uranyl nitrate-induced acute renal failure rats

“…However, in the present rat study, the F was estimated for comparison based on AUC after IV and AUC 0-8 h after oral studies; the F value was considerably decreased in the U-ARF rats; 8.53 and 3.67% for the control and U-ARF rats, respectively. Low F, 10-19%, was also reported in humans due to the high first-pass metabolism of azosemide [3,27]. Liver and stomach had considerable metabolic activities for azosemide after 30 min incubation of azosemide with 9000 g supernatant fraction of rat tissue homogenates [9].…”

A Micellar Liquid Chromatographic Method for the Determination of Azosemide in Solubilized System

“…Azosemide (AZS) (Fig. 1) is a novel long-acting loop diuretic which acts qualitatively as a drug for prolonging the diuretic effect [1][2][3]. It is a new monosulfamyl diuretic widely used in the management of various conditions [4][5][6] such as cirrhosis of the liver [7,8], rennin and aldosterone inhibition [9], hypertension [10], heart rate variability and failure [11,12] and traumatic subarachnoidal hemorrhage [13,14].…”

Gender differences in pharmacokinetics and pharmacodynamics of azosemide in rats

“…This could be due to the high first-pass metabolism of azosemide after oral administration [3], and hence its low oral bioavailability (extent) in humans; which ranges from 10 to 19% [4]. After intravenous and oral administration of azosemide in humans, 17-37% and less than 10% of the dose, respectively, were recovered in urine as unchanged azosemide [6]. Recently, it was reported [7] that most of the orally administered azosemide disappeared (mainly due to metabolism) by intestine (intestinal first-pass effect) in rats.…”