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PubMedDate not supplied

Pharmacokinetics of furosemide after three different single oral doses.

Furosemide solution was orally administered to 21 healthy adult males to determine dose proportionality over the dose range used and the reproducibility of disposition following a repeated dose. Furosemide solution was given in doses of 20, 40, and 80 mg, with the 40 mg dose repeated once. Blood was collected for 12 hours post-dose and urine for 24 hours. The maximum plasma concentrations resulting from 20, 40, and 80 mg doses were significantly different (p less than 0.05). Dose normalized maximum concentrations for the 20 and 80 mg doses were significantly different (p less than 0.05). Mean time to Cpmax was 50 minutes, with no differences observed among doses. Plasma AUCs were significantly different (p less than 0.05) for 20, 40, and 80 mg. Dose normalized AUCs were not significantly different. Mean amounts of furosemide in urine (Xu) were 9.62, 16.7, and 32.0 mg for the 20, 40, and 80 mg doses, respectively. These amounts were significantly different (p less than 0.05); dose normalized amounts were not significantly different. Renal clearances of furosemide following the three doses were not significantly different. Regressions of Cpmax, AUC and Xu on dose were significant. There were no significant differences in Cpmax, tmax, AUC or Xu for 40 mg given on two separate days. Renal clearance of furosemide was statistically different for 40 mg given on two separate days, but the difference was not clinically significant. The pharmacokinetics of furosemide are linear over the dosage range studied. Furosemide 40 mg given on two separate days results in similar disposition parameters.

Administration, Oral↗

PubMed1978

Effects of probenecid on furosemide response.

Furosemide gains access to its intraluminal site of action by active secretion by the organic acid transport system of the proximal tubule. Inhibition of this transport by probenecid would predictably decrease the effect of furosemide. In this study in 8 normal volunteers, however, the opposite occurred; namely, pretreatment with probenecid increased the overall response to furosemide by prolonging its effect. Sodium excretion in 8 hr due to 40 mg of furosemide rose from 262 +/- 16 to 358 +/- 11 mEq after probenecid. Urine volume increased from 3,265 +/- 275 to 4,165 +/- 183 ml after probenecid. Analysis of the time-course of the increased diuresis and natriuresis showed that probenecid actually decreased the response for the first 60 to 90 min after furosemide but increased the subsequent response sufficiently to result in a greater overall effect. Possible explanations include access of furosemide to its active site from the serum, an effect of probenecid on prostaglandin transport, and a changing pharmacokinetic interaction between probenecid and furosemide.

Adult↗

PubMed1979

Effect of furosemide on plasma concentration and beta-blockade by propranolol.

Although propranolol and furosemide are used together for hypertension, the effects of furosemide on plasma levels and beta-blocking action of propranolol are not known. Ten healthy subjects received propranolol 40 mg orally; the mean plasma propranolol levels in 60, 90, 180, and 300 min were 85 +/- 16, 90 +/- 7, 82 +/- 8, and 58 +/- 8 ng/ml. Propranolol was then given together with furosemide (25 mg orally) and the propranolol blood level was measured. Mean propranolol plasma levels were 106 +/- 11 ng/ml at 60 min, 120 +/- 12 ng/ml at 90 min (p less than 0.01), 102 +/- 8 ng/ml at 180 min (p less than 0.05), and 78 +/- 8 ng/ml at 300 min (p less than 0.01). Six additional subjects were given an infusion of 1 microgram/min isoproterenol increased by 0.5 microgram/min every 2 min until the heart rate rose by 25% after oral administration of furosemide 25 mg. This procedure was repeated after propranolol (40 mg orally) and propranolol with furosemide (25 mg orally). The amount of isoproterenol which raised the heart rate by 25% was 2.6 +/- 0.3 micrograms after furosemide alone and 17.7 +/- 2 micrograms after propranolol (p less than 0.01). After propranolol with furosemide the dose of isoproterenol required to elevate heart rate by 25% was 109 +/- 15 micrograms (p less than 0.001).

Adolescent↗

PubMedDate not supplied

Comparative acute cochlear toxicity of intravenous bumetanide and furosemide in the purebred beagle.

Comparisons were made of the effects of various doses of intravenous bumetanide and furosemide on the primary auditory afferent activity (N1) and cochlear microphonics (CM) of beagles. The dose-response relationships of the N1 depressions to bumetanide and furosemide are parallel; those of the CM depressions are also parallel but have a much shallower slope than those of the N1 depressions. With both drugs, N1 depression occurs at lower doses than does CM depression. The N1 depression produced by a particular dose of bumetanide or furosemide bore a linear relationship to the CM depression produced. This finding supports the postulate that the cochlear site and mechanism of ototoxic action of the loop diuretics are directed at an earlier step of the cochlear transduction process than N1. Using N1 depression as the gross electrophysiologic index of ototoxicity, the acute ototoxic potency of bumetanide in beagles is approximately 6.5 times that of furosemide, whereas its diuretic potency is 40 to 60 times that of furosemide. Therefore, when clinical dosages of the two drugs are considered, the relative acute ototoxic potency of bumetanide in the beagle is 0.11 to 0.16 that of furosemide. This range is identical to the relative ototoxic potency of 0.11 to 0.16 previously obtained in the cat. Serum concentrations of bumetanide and furosemide increased linearly with the doses of the two drugs, except for the highest dose given (100 mg/kg for both drugs). The serum concentrations at that dose of both drugs are less than the mathematically predicted values. Histologic (light-microscopic) examination of the cochleas did not reveal any significant pathology.

Animals↗

PubMed1993

Influence of lisinopril on urinary electrolytes excretion after furosemide in healthy subjects.

It has been reported that the urinary excretions of chloride (Cl), potassium (K), and magnesium (Mg), but not sodium (Na), after furosemide, a loop diuretic, were decreased by pretreatment with lisinopril, an ACE inhibitor in hypertensive subjects. The electrolytes disturbance induced by furosemide might be ameliorated by lisinopril. The present study re-examines this potential drug interaction in healthy subjects. Lisinopril (20 mg) or its matching placebo was given orally using a double-blind, crossover design. Four hours after lisinopril administration, furosemide (20 mg) was injected intravenously and urine was collected during the following intervals: 0-0.5, 0.5-1, 1-1.5, 1.5-2, 2-3, 3-4, and 4-6 hours. Blood samples for plasma furosemide concentration were obtained at 0.5, 1, 1.5, 2, 3, 4, and 6 hours after the agent. There were no significant differences between the two trials in plasma concentrations of furosemide or urinary excretions of the agent. Urine volume and urinary excretions of electrolytes (Na, Cl, K, and Mg) after the furosemide with lisinopril administration were not significantly different from those of placebo at any observation period. These results suggest that the urinary excretions of electrolytes after furosemide administration are not influenced by pretreatment with lisinopril.

Adult↗

PubMed1996

The effects of epoprostenol on drug disposition. II: A pilot study of the pharmacokinetics of furosemide with and without epoprostenol in patients with congestive heart failure.

The effect of epoprostenol on the pharmacokinetics of furosemide was investigated in 23 patients with end-stage congestive heart failure (CHF) receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of the apparent oral clearance, volume of distribution, and absorption rate constant for furosemide were generated from 198 serum furosemide concentrations using nonlinear mixed effects modeling (NONMEM). Univariate analyses were performed to assess the effects of patient factors on the apparent oral clearance of furosemide. The final multivariate model determined by backwards elimination included concomitant digoxin therapy. When concomitant epoprostenol therapy was included in the final model, there was a 13% decrease in the apparent oral clearance of furosemide in response to short-term administration of epoprostenol. However, the effect of concomitant epoprostenol therapy was not statistically significant and was no longer apparent by the end of the 12-week study. These data suggest that epoprostenol may have a slight short-term effect on the pharmacokinetics of furosemide; the interaction between epoprostenol and furosemide is not clinically significant, however.

Diuretics↗

PubMed1994

Reversal of bronchial obstruction in children with mild stable asthma by aerosolized furosemide.

Aerosolized furosemide has been shown to prevent the worsening of different variables in pulmonary function testing, following exercise or bronchial provocation with numerous agents. To investigate if aerosolized furosemide has a bronchodilator effect, we performed two prospective, randomized, placebo-controlled, double-blinded and crossover studies of four aerosol regimens in children with mild chronic asthma. In a pilot study examining three different doses of furosemide in 11 children, the dose of 1.0 mg/kg resulted in a mean maximum increase of 30.0 +/- 6.8% in forced expiratory flow between 25 and 75% vital capacity (FEF25-75), compared with a 3.1 +/- 6.8% increase after aerosolized normal saline. The effect was observed after 10 minutes with a mean percent change of 17.7 +/- 1.7% from baseline, that persisted to 30 minutes (19.3 +/- 3.7%) and was significantly greater than that seen following aerosolized placebo (1.4 +/- 2.9% and 0.7 +/- 3.4%, respectively; P < 0.05). We then compared the effect of furosemide with that of aerosolized albuterol (0.15 mg/kg) in 18 patients. There was no statistically significant difference in the improvement observed in forced expiratory volume in 1 second (FEV1) for albuterol (15.0 +/- 2.7%) compared with furosemide (12.1 +/- 2.9%) or in FEF25-75 (42.9 +/- 9.0% versus 26.3 +/- 6.7%). The addition of albuterol to furosemide resulted in a 17.2 +/- 5.9% increase in FEV1 and a 51.1 +/- 13.9% increase in FEF25-75. Our results indicate that aerosolized furosemide has a bronchodilator effect in children with mild stable asthma.

Administration, Inhalation↗

PubMed1986

Diuretic activity of torasemide and furosemide in chronic heart failure: a comparative double blind cross-over study.

The diuretic effects of torasemide and of furosemide were compared in a double blind cross-over study in 13 patients with stable chronic heart failure. Single doses of 10 mg and 20 mg of torasemide and of 40 mg of furosemide were given orally, in a randomized order on 3 consecutive days. In addition, a placebo was administered on the day preceding the 3 active drug treatment days to obtain control data. Each experimental day was divided into three urine collection periods - 0 to 4 h, 4 to 12 h and 12 to 24 h. Urine output, ion excretion and clearance were measured during each of the 3 periods as well as for the 24-h period. Torasemide 20 mg was distinctly more active in each of the 3 collection periods and in the 24-h period than furosemide 40 mg, whereas no significant difference was found between furosemide 40 mg and torasemide 10 mg for most of the experimental data. From 0 to 4 h, both torasemide and furosemide significantly increased the urinary flow rate and the urinary excretion of sodium, chloride and calcium, while they decreased the urinary osmolality when compared to placebo. All the effects persisted in the 4 to 12 h period after torasemide 20 mg in contrast to furosemide, whose effects were limited to the 0 to 4 h period. In the third period (12-24 h), the urine volume fell below the placebo value after furosemide but not torasemide, and only torasemide 20 mg was followed by a persistent decrease in the urine osmolality.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1982

Pharmacokinetics of furosemide in patients with hepatic cirrhosis.

The pharmacokinetics of furosemide was studied in 7 patients with diagnosed liver cirrhosis and in 7 healthy subjects. Furosemide in plasma and ascitic fluid was analyzed spectrofluorometrically. After a single intravenous dose, the cirrhotic patients showed lower initial plasma concentrations of furosemide because of the larger volume of distribution. The mean half-life in cirrhotic patients was significantly greater than in healthy volunteers. The longer half-life was associated with a reduction in the serum clearance of furosemide. Ascitic fluid volume in the patients ranged from 4.6 to 7.71. There was no significant amount of furosemide in the fluid. The diuretic interchange between this fluid and plasma was slow, as peak concentrations ranged from 0.3 to 0.5 microgram/ml within 3 to 5 h after bolus administration of furosemide. Diuresis and urinary sodium excretion, 5 h after furosemide injection, were similar in both groups; larger potassium excretion was found in the cirrhotic patients.

Adult↗

PubMed1977

Distribution, elimination and effect of furosemide in normal subjects and in patients with heart failure.

After furosemide 40 mg i. v. its plasma concentration was significantly higher during an 8-hour period in 6 patients with left sided heart failure than in 8 normal subjects. The plasma clearance was significantly lower in the patients than in the normal subjects--1.23 and 2.34 ml/kg/min, respectively. The apparently smaller volume of distribution in the cardiac patients (0.140 1/kg and 0.181 1/kg, respectively) was not significantly different. In the group of normal subjects, whose ages ranged from 27 to 74 years, no correlation was found between age and either plasma clearance or volume of distribution. In all the patients, the renal clearance of furosemide rose from the first to the second hour after the injection (average +/- SD)--39 +/- 17 and 77 +/- 51 ml/min. In normal subjects, the average values did not change--116 +/- 79 and 117 +/- 54 ml/min. The urinary excretion of furosemide and a metabolite (probably a glucuronide) was measured in 16 individuals. 24-hour urines from all the subjects investigated contained between 20 and 30 mg unchanged furosemide (average 25.2 mg). In addition, between 2.7 and 11.2 mg (average 6.7 mg) furosemide was excreted as the metabolite in five patients who had been treated with furosemide for at least the preceding 6 months. An average of 0.8 +/- 0.8 mg of the metabolite was found in 11 subjects who had not previously been treated with furosemide.

Adult↗

PubMed1980

Studies with the optically active isomers of the new diuretic drug ozolinone. II. Inhibition by d-ozolinone of furosemide-induced diuresis.

The effect of the non-diuretic dextrorotatory isomer of ozolinone on furosemide-induced diuresis was studied by means of clearance and micropuncture techniques in rats. After intravenous injection, d-ozolinone antagonized the furosemide-induced increase in renal fluid and electrolyte excretion in a dose-related manner. Microperfusion experiments of Henle's loop in vivo revealed that d-ozolinone did not interfere with the action of furosemide at this tubular site. However, d-ozolinone markedly decreased the furosemide to inulin clearance ratio, presumably as a consequence of inhibition of furosemide secretion into the proximal tubules. It is assumed that, in consequence of a high affinity for the proximal organic acid transport system, d-ozolinone depresses proximal tubular furosemide secretion and prevents transfer of this diuretic to the tubular fluid. Thus, under the influence of d-ozolinone, furosemide cannot reach the loop of Henle in sufficient amounts and its diuretic effect is blocked.

Animals↗

PubMed1975

On the fate of furosemide in man.

35S-furosemide was administered orally (n=7) or i.v. (n=2) to healthy subjects. The average gastrointestinal uptake estimated by comparison of the urinary recovery of label and the areas under the plasma curves after the two routes of administration was 65%. The half life of radioactivity in the plasma after oral 35S-furosemide was 90 +/- 17 min (estimated on the slope between 2 and 6 h); the corresponding figure after 35S-furosemide i.v. was 47-53 min (slope 0.5-4 h). There was probably a slower phase after 4-6 h. Fractionation of labelled material in urine from two subjects demonstrated that approximately two thirds of the label recovered at 24 h had the same chromatographic properties as furosemide. A major part of the metabolite(s) was probably furosemide glucuronide. There was no evidence that 4-chloro-5-sulfamoylanthranilic acid was formed in man. The total urinary recovery of label (5-7 d) after oral and intravenous administration was 55.1 +/- 3.2 (mean +/- SD) and 82-84%, respectively. After 35S-furosemide i.v., 6-9% of the label was recovered in faeces, and it could not be accounted for solely by biliary excretion of furosemide.

Administration, Oral↗

PubMed1984

Pharmacokinetic and pharmacodynamic study of the combination of furosemide retard and triamterene.

The pharmacodynamics and pharmacokinetics of the combination of furosemide retard (30 mg)/triamterene (50 mg) were compared with furosemide (30 mg) in 18 healthy male volunteers aged 39.3 +/- 6.3 years. After the administration of furosemide the onset of its effect was very rapid, reaching a maximum between 1.5 to 3 h, and followed by rebound after 9 to 10.5 h. In contrast the combination furosemide retard/triamterene showed a protracted course with a duration of effect up to 12 h. The general effect over 12h of the two preparations was equivalent with respect to the excretion of urine, sodium, chloride and calcium, but the combination caused significantly less excretion of potassium (p less than or equal to 0.05) than furosemide. After a lag-phase of 33.9 +/- 5.4 min the maximum plasma concentration of furosemide was reached after 3.47 +/- 0.66 h, and the elimination half-life was approximately 2 h. After a lag-phase of 33.0 +/- 17.8 min the maximum plasma concentration of the main metabolite of triamterene, the OH-TA sulphuric acid ester, was reached after 1.7 +/- 0.59 h, and its elimination half-life amounted to 1.25 +/- 0.37 h. Because of the sustained release of furosemide from the retard-formulation, its principal pharmacokinetic parameters were better adapted to those of triamterene. The consequences were not only a protracted effect but also an improved electrolyte profile, especially with regard to reduced loss of potassium. In the case of renal insufficiency, however, the potassium level in serum might be increased to an undesirable extent.

Adult↗

PubMed1985

Bioavailability and diuretic effect of furosemide during long-term treatment of chronic respiratory failure.

The bioavailability and diuretic effect of furosemide 40 mg administered orally for at least 6 months have been compared in patients with chronic respiratory failure and in healthy controls. The mean urinary recovery of unchanged drug was 11.5 mg and 9.41 mg in 24 h after pre- and postprandial administration to 10 patients, whereas the recovery was 14.4 mg in 10 healthy subjects. The diuretic effect, in terms of urine flow and sodium ion excretion in the 6 h after administration, was also less in patients than in healthy subjects. This was ascribed to the lower bioavailability of furosemide in patients, based on the urinary recovery of unchanged drug, and not to a lower level of response to furosemide than in healthy subjects. The mean absolute bioavailability of furosemide in 6 patients was 41.3% and 63.4%, respectively, calculated from unchanged drug and total drug (unchanged plus glucuronide conjugate). Approximately 53.9% of the dose of furosemide was excreted as the glucuronide conjugate after oral administration, and 34.2% after i.v. injection in the 6 patients. In 3 of the 6 patients studied, a distinct first-pass effect for glucuronidation of furosemide was observed after oral administration. In another study, the mean glucuronide fraction recovered in 24-h urine was 20.7% and 7.3% (p less than 0.01) in 38 patients and 12 healthy subjects, respectively. The fraction in urine was not affected by changing the dose of furosemide from 20 to 120 mg. The lower bioavailability in patients as compared to healthy subjects is ascribed to enhanced glucuronidation and incomplete drug absorption.

Administration, Oral↗

PubMed1996

Histological long-term outcome of furosemide-induced nephrocalcinosis in the young rat.

The long-term prognosis of furosemide-associated nephrocalcinosis in the infant is still unclear. Although discontinuation of the diuretic often results in radiological resolution of the calcifications, functional abnormalities may persist. The natural history of the renal histopathology of these patients is yet unknown. In the present study we investigated the histological long-term outcome of furosemide-induced nephrocalcinosis in the young rat. Thirty-six weanling male Sprague-Dawley rats were divided into three groups: A controls, B furosemide given for 8 weeks, and C furosemide given for 2 weeks followed by 6 weeks of observation. Metabolic studies at the end of the experiment demonstrated a significant diuretic and natriuretic effect in group B. Kidney histology showed nephrocalcinosis scores (mean +/- SD) of 0.0 +/- 0.0 in A, 2.6 +/- 1.5 in B, and 0.8 +/- 0.6 in C, with B significantly higher than A and C, and C greater than A. Kidney calcium content in B (3,421.9 +/- 2,558.7 micrograms/g dry tissue) was significantly greater than in A (310.4 +/- 21.3) and C (1470.1 +/- 932.2). Another group of 6 rats receiving 2 weeks treatment of furosemide showed a nephrocalcinosis score of 2.2 +/- 1.5, not different from group B, and an additional group of 6 rats treated with furosemide for 2 weeks and observed for another 12 weeks showed a score of 1.3 +/- 0.4, not different from group C. We conclude that most of the renal calcifications induced by furosemide occur during the early days of treatment and that up to 12 weeks after discontinuation of the diuretic, the resolution of the calcifications is only partial.

Animals↗

PubMed1995

Furosemide dynamics in conscious rabbits: modulation by arginine vasopressin.

The aims of this study were to assess the influence of arginine-vasopressin (AVP) on the pharmacodynamics and kinetics of furosemide. To this purpose, the response and the kinetics of furosemide (5 mg/kg i.v.) were studied in two groups of rabbits, one control and one receiving an infusion of AVP (2.5 ng/kg/min). The infusion of AVP generated mean plasma levels of 35 pg/ml, and in these rabbits osmolal clearance was increased, free water clearance was reduced, and renal plasma flow was reduced by 25% (p < 0.05). High AVP plasma levels increased the natriuresis (p < 0.01) and the urinary excretion of prostaglandin E2 (UPgE2V; p < 0.01). The increase in UPgE2V was associated with AVP plasma concentrations (r = 0.8248; p < 0.001). AVP reduced the increment in natriuresis and diuresis elicited by furosemide from 163 +/- 20 to 87 +/- 20 mumol/min (p < 0.05) and from 1.22 +/- 0.11 to 0.83 +/- 0.13 ml/min (p < 0.05). The infusion of AVP enhanced furosemide metabolic clearance but diminished its renal clearance, resulting in a decrease in the rate of furosemide urinary secretion. It was concluded that high plasma levels of AVP reduce furosemide natriuresis, presumably because of a decrease in furosemide urinary secretion.

Analysis of Variance↗

PubMed1995

Furosemide dynamics in conscious rabbits: modulation by angiotensin II.

The aim of this study was to investigate the effects of an infusion of angiotensin II (50 ng/kg/min) on furosemide pharmacodynamics and kinetics in the conscious rabbit. The protocol included a 90-minute phase to estimate the glomerular filtration rate and the renal plasma flow, followed by a 60-minute phase where 5 mg/kg (n = 12) or 10 mg/kg (n = 9) of furosemide were administered. During the pre-furosemide phase, compared to control rabbits, angiotensin II increased natriuresis and diuresis. In the presence of angiotensin II, the furosemide-induced natriuresis decreased, that is, it was 174 +/- 14 versus 95 +/- 25 mumol/min (p < 0.05) and 187 +/- 17 versus 89 +/- 21 mumol/min (p < 0.05) for the 5 and the 10 mg/kg doses, respectively. The infusion of angiotensin II decreased renal plasma flow without modifying the glomerular filtration rate, thus the filtration fraction was increased. Angiotensin II increased the area under the furosemide plasma concentrations as a function of time since it decreased its systemic clearance. However, furosemide urinary excretion rate was not altered and its renal clearance decreased slightly without reaching statistical significance. It is concluded that angiotensin II decreases the response to furosemide and the mechanism underlying this effect is related to the pharmacodynamics rather than the kinetics of the diuretic.

Angiotensin II↗

PubMed1979

Pharmacokinetics/pharmacodynamics of furosemide in man: a review.

The pharmacokinetics of furosemide and the attempt to correlate biological fluid measurements with diuretic response have been the subject of a large number of studies since the original reports of Hajdú, Rupp, and coworkers in the mid-1960s. This article attempts to critically review these studies under seven different sections: furosemide pharmacokinetics in normal volunteers, furosemide pharmacokinetics in patients with decreased renal function, furosemide pharmacokinetics in patients with congestive heart failure, furosemide metabolism and assay methods, furosemide bioavailability, dose-response relationships, and the role of inhibitors and mediators on furosemide effects. The literature is reviewed through August 1978.

Biological Availability↗