Urinary Excretion Of Furosemide Research Articles

Efficacy of furosemide-albumin compared with furosemide in critically ill hypoalbuminemia patients admitted to intensive care unit: a prospective randomized clinical trial.

Some physicians co-administer albumin with loop diuretics to overcome diuretic resistance in critically ill hypoalbuminemia patients, though previous studies have reported conflicting results on this matter. The effects of adding albumin to furosemide to enhance its efficacy in critically ill hypoalbuminemia patients are evaluated. This was a non-blinded randomized trial. 49 adult critically ill patients with hypoalbuminemia and generalized edema who received randomly furosemide and furosemide/albumin complex were enrolled. The patients' urine was collected at intervals of 2, 4, 6 and 8h after initiation of the furosemide treatment, and the urine output and urinary excretion of furosemide and sodium were measured. The urinary excretion of furosemide was considered an indicator of drug efficacy. The amount of sodium and furosemide excreted in urine showed no significant differences between the two groups; however, the mean of the urinary excretion of furosemide in the first 2h after drug infusion was significantly higher (p = 0.03) in the furosemide/albumin group. No significant correlation between APACHE II scores and serum albumin levels and the urinary excretion of furosemide was seen. The results indicated that there is not statistically significant differences between groups with furosemide alone and combined with albumin in urinary furosemide excretion. It seems that adding albumin for furosemide pharmacotherapy regime is not recommended as an intervention to increase furosemide efficacy in critically ill hypoalbuminemia patients. IRCT with the registration number IRCT201412132582N12 in 23 February 2015; https://en.irct.ir/trial/2356 Graphical abstract.

Population‐based meta‐analysis of furosemide pharmacokinetics

Furosemide is a loop diuretic frequently used to treat fluid overload conditions such as hepatic cirrhosis and congestive heart failure (CHF). A population-based meta-analysis approach in NONMEM® was used to develop a PK model characterizing the time-course of furosemide in plasma and excretion into the urine for healthy subjects and fluid overload patients. Furosemide PK data from healthy subjects receiving 80 mg of oral furosemide were supplemented with additional individual and aggregate plasma concentration and urinary excretion versus time data from the literature after intravenous (i.v.) or oral furosemide administration (10-500 mg) to healthy subjects or fluid overload patients. A three-compartment model with zero-order input following i.v. administration (or first-order absorption using a Weibull function after oral administration) and first-order elimination best described furosemide PK. A covariate analysis identified creatinine clearance (CL(CR)) as a statistically significant predictor of renal clearance (CL(R)), with a population mean CL(R) of 4.67, 3.11, 1.95 and 1.17 l/h for a subject with normal renal function (CL(CR) = 120 ml/min) or mild (CL(CR) = 80 ml/min), moderate (CL(CR) = 50 ml/min) or severe (CLCR = 30 ml/min) renal impairment. Oral bioavailability was 59.1% and non-renal clearance was 2.02 l/h. A PC-VPC and other model diagnostics demonstrated that the population PK model can reasonably predict the rate of urinary furosemide excretion over time using dosing history and commonly available demographic data, allowing for convenient assessment of PK-PD relationships for furosemide when given alone or in combination with other agents used to treat fluid overload conditions.

Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics

Organic anion transporter (OAT) genes have been implicated in renal secretion of organic anions, but the individual in vivo contributions of OAT1 (first identified as NKT) and OAT3 remain unclear. Potential substrates include loop diuretics (e.g., furosemide) and thiazide diuretics (e.g., bendroflumethiazide), which reach their tubular sites of action mainly by proximal tubular secretion. Previous experiments in Oat1 knockout (-/-) mice revealed an almost complete loss of renal secretion of the prototypic organic anion p-aminohippurate (PAH) and a role of OAT1 in tubular secretion of furosemide (Eraly SA, Vallon V, Vaughn D, Gangoiti JA, Richter K, Nagle M, Monte JC, Rieg T, Truong DM, Long JM, Barshop BA, Kaler G, Nigam SK. J Biol Chem 281: 5072-5083, 2006). In this study we found that both furosemide and bendroflumethiazide inhibited mOat1- and mOat3-mediated uptake of a labeled tracer in Xenopus oocytes injected with cRNA, consistent with their being substrates for mouse OAT1 and OAT3. Experiments in Oat3(-/-) mice revealed intact renal secretion of PAH, but the dose-natriuresis curves for furosemide and bendroflumethiazide were shifted to the right and urinary furosemide excretion was impaired similar to the defect in Oat1(-/-) mice. Thus, whereas OAT1 (in contrast to OAT3) is the classic basolateral PAH transporter of the proximal tubule, both OAT1 and OAT3 contribute similarly to normal renal secretion of furosemide and bendroflumethiazide, and a lack of either one is not fully compensated by the other. Although microarray expression analysis in the kidneys of Oat1(-/-) and Oat3(-/-) mice revealed somewhat altered expression of a small number of transport-related genes, none were common to both knockout models. When searching for polymorphisms involved in human diuretic responsiveness, it may be necessary to consider both OAT1 and OAT3, among other genes.

Multidrug Resistance–Associated Protein 4 Is Involved in the Urinary Excretion of Hydrochlorothiazide and Furosemide

The role of ATP-binding cassette transporters in the urinary excretion of diuretics was investigated. Significant ATP-dependent uptake of hydrochlorothiazide (HCT) and furosemide was observed in membrane vesicles that expressed multidrug resistance-associated protein 4 (MRP4) and breast cancer resistance protein (BCRP). Unlike taurocholate uptake, S-methylglutathione had no effect on the ATP-dependent uptake of both compounds by MRP4. The functional importance of MRP4 and BCRP in the urinary excretion of HCT and furosemide was investigated using gene knockout mice. The renal clearance of HCT and furosemide was reduced significantly but not abolished in Mrp4 knockout mice compared with wild-type mice (9.0 +/- 0.9 versus 15 +/- 2 ml/min per kg for HCT and 1.9 +/- 0.3 versus 2.7 +/- 0.1 ml/min per kg for furosemide), and the amount of HCT that was associated with the kidney specimens was greater in Mrp4 knockout mice (21 +/- 3 versus 13 +/- 1 nmol/g kidney). In contrast, Bcrp makes only a negligible contribution because the urinary excretion was unchanged in Bcrp knockout mice. Our results suggest that Mrp4, together with other unknown transporters, accounts for the luminal efflux of HCT and furosemide from proximal tubular epithelial cells.

Characterizing variability in cardiovascular drug responses

Characterizing variability in cardiovascular drug responses

Acute Effects of High-Dose Furosemide on Residual Renal Function in CAPD Patients

♦ Background High doses of furosemide can increase urine volume in chronic peritoneal dialysis (CAPD) patients. However, no information is available about effects on urinary solute excretion in relation to residual glomerular filtration rate (GFR), urinary furosemide excretion, and peritoneal solute kinetics. ♦ Methods Diuretic response and the effect on peritoneal fluid and solute transport parameters were investigated in 7 stable CAPD patients with residual renal function (median urine volume 350 mL/24 hours, range 140–1900 mL/24 hours). Comparisons were made during two clearance periods of 24 hours: one without (P1) and one during 2 g furosemide (P2). ♦ Results The median increase in urine volume was 400 mL (range 270 – 910 mL, p < 0.02) and the increase in sodium excretion was 54 mmol (range 25 –118 mmol, p < 0.02). No change in GFR was found between P1 (2.4 mL/minute, range 0.6 – 5.7 mL/min) and P2 (2.0 mL/min, range 1.0 – 4.8 mL/min). An increase in fractional clearance was found for volume, sodium, potassium, and osmolality ( p < 0.02). No change was found in the fractional clearance of urea and electrolyte-free water. Furosemide excretion in urine was 8.7 mg/24 hours (range 2.1 – 38 mg/24 hours) and in dialysate 4.9 mg/24 hours (range 1.9 – 7.8 mg/24 hours). Plasma furosemide concentration was 29.5 mg/L (range 6.2 – 43.9 mg/L). A positive correlation was found between residual GFR and total urine furosemide excretion ( r=0.93, p < 0.005). Efficiency, expressed as the increase in fractional sodium clearance (percent) per milligram of furosemide excreted per 24 hours, was 1.2%/mg (range 0.3%–11.3%/mg). ♦ Conclusion High-dose furosemide is effective in CAPD patients in increasing urine volume and electrolyte excretion without affecting urea and creatinine clearance. In CAPD patients, the individual response to an identical high dose of furosemide is dependent on the magnitude of residual GFR.

Determination of furosemide in urine samples by direct injection in a micellar liquid chromatographic system.

A sensitive, selective and efficient micellar liquid chromatographic (MLC) procedure was developed for the determination of furosemide (4-chloro-N-furfuryl-5-sulfamoylanthranilic acid) in urine samples by direct injection and UV detection. The procedure makes use of a C18 reversed-phase column and a micellar mobile phase of 0.05 mol l(-1) sodium dodecyl sulfate-6% v/v propanol and phosphate buffer at pH 3 to resolve furosemide from its photochemical degradation products. The importance of protecting the standards and urine samples to be analysed from light in the assay of furosemide, avoiding its degradation, was verified. The limit of quantification was 0.15 microg ml(-1) and the relative standard deviation of the inter-day assay was 0.8-0.04% in the 6-82 microg ml(-1) range. Detection of urinary excretion of furosemide was followed up to 12 h after ingestion of the drug by a healthy volunteer. No potential interference from the major metabolite (furosemide acylglucuronide) and its hydrolytic product (4-chloro-5-sulfamoylanthranilic acid) was observed. Commonly administered drugs also did not interfere. The proposed MLC procedure permits the rapid and reproducible measurement of low levels of furosemide in a small amount of urine.

Effects of albumin/furosemide mixtures on responses to furosemide in hypoalbuminemic patients.

Hypoalbuminemic patients often have sufficient fluid accumulation to mandate diuretic therapy but are often resistant to diuresis. Studies have suggested that hypoalbuminemia itself impairs delivery of effective amounts of diuretic agent into the urine, the site of action. Therefore, administration of mixtures of albumin and loop diuretics may enhance responses. Thirteen patients with biopsy-proven cirrhosis and ascites (age, 51.2 +/- 8.1 yr; Child-Pugh score, 8.5 +/- 1.0; serum albumin concentration, 3.0 +/- 0.6 g/dl) were studied in this randomized crossover study. Sodium balance was maintained throughout the study with a metabolic diet. All patients received spironolactone, but administration of all other diuretic agents was discontinued. Each patient received all of the following four treatments intravenously: (1) 40 mg of furosemide, (2) 25 g of albumin, (3) 40 mg of furosemide and 25 g of albumin premixed ex vivo, and (4) 40 mg of furosemide and 25 g of albumin infused simultaneously into different arms. Responses were assessed by measuring urinary sodium excretion and relating the urinary furosemide excretion rate to the sodium excretion rate. Additionally, the pharmacokinetics of furosemide were assessed. Furosemide pharmacokinetics were similar for all treatment arms. Albumin alone had negligible diuretic effects. Neither albumin regimen increased the response to furosemide. Moreover, the relationship between the urinary furosemide excretion rate and the sodium excretion rate was unaffected by albumin. In conclusion, albumin failed to enhance the diuretic effects of furosemide in cirrhotic patients with ascites. Therefore, the coadministration of albumin and furosemide for the treatment of cirrhosis, and likely other hypoalbuminemic conditions, should not be used clinically.

An in vitro-in vivo investigation of oral bioadhesive controlled release furosemide formulations

The in vitro controlled release and bioadhesive properties of furosemide formulations were evaluated with standard dissolution tests and with a specially developed model using rabbit intestine. The results showed that the controlled release properties were not affected by the application of the bioadhesive polymer but that the bioadhesive properties were substantially different. In order to assess the gastrointestinal transit time in vivo, a γ-scintigraphy study was performed in six volunteers testing the same controlled release formulation with and without bioadhesive polymer. Plasma levels of furosemide, evaluation of urinary flux and measures of urinary excretion of furosemide in the six volunteers allowed correlations to be made between gastrointestinal transit and furosemide absorption.

The influence of moderate hypoalbuminaemia on the renal metabolism and dynamics of furosemide in the rabbit.

1. The present study aimed to investigate the influence of hypoalbuminaemia on the pharmacokinetics and pharmacodynamics of furosemide. Hypoalbuminaemia was produced by repeated plasmapheresis, to attain plasma albumin concentrations of 21.6 +/- 0.9 g l-1, compared with 33.0 +/- 0.6 g l-1 in controls (P < 0.001). The per cent of bound furosemide in hypoalbuminaemic rabbits (90.8 +/- 0.7%) was lower than that in control rabbits (97.4 +/- 0.5%, P < 0.001). The kinetics of intravenous furosemide (2.5 mg kg-1) were studied in control (n = 6) and hypoalbuminaemic rabbits (n = 6). 2. To assess the effect of hypoalbuminaemia on extrarenal clearance of furosemide, functional anephria was induced by ligating the renal pedicles of 12 rabbits, which were segregated in two groups, with and without hypoalbuminaemia. 3. In the control group, total, urinary and metabolic clearances of furosemide were 11.8 +/- 1.0, 5.0 +/- 0.4 and 6.8 +/- 0.6 ml min-1 kg-1, respectively. Compared with control rabbits, in hypoalbuminaemic rabbits, total clearance of furosemide increased by 40% (P < 0.001), result of the enhancement of furosemide metabolic clearance (C1m) from 5 to 10 ml min-1 kg-1 (P < 0.01). In hypoalbuminaemic rabbits, urinary excretion of furosemide was reduced by 26% (2451 +/- 115 vs 1818 +/- 134 micrograms h-1, P < 0.01). In anephric rabbits, furosemide total clearance was 1.77 +/- 0.12 ml min-1 kg-1, value not affected by hypoalbuminaemia, confirming that the increase in C1m induced by hypoalbuminaemia occurs in the kidneys. 4. Compared with controls, in hypoalbuminaemic rabbits, the rate of urinary excretion (142 +/- 9 vs 74 +/- 8 ml h-1, P < 0.001) and the rate of excretion of sodium (18.6 +/- 0.9 vs 9.9 +/- 0.9 mmol h-1, P < 0.001) were very much reduced. However, the dose-response curves were not different. 5. In conclusion, hypoalbuminaemia is associated with an increase in renal metabolic clearance of furosemide, possibly because of the increase in furosemide unbound concentration, and a decrease in the diuretic/natriuretic effect of furosemide, secondary to a reduction in furosemide tubular secretion. Thus, albumin facilitates the renal secretion of organic anions but not their metabolism.

Diuretic efficacy of high dose furosemide in severe heart failure: Bolus injection versus continuous infusion

The efficacy of high dose furosemide as a continuous infusion was compared with a bolus injection of equal dose in patients with severe heart failure. The delivery rate of furosemide into the nephron has been proved to be a determinant of diuretic efficacy in healthy volunteers. In a randomized crossover study we compared the efficacy of a continuous infusion of high dose furosemide (mean daily dosage 690 mg, range 250 to 2,000) versus a single bolus injection of an equal dose in 20 patients with severe heart failure. The patients received an equal dosage, either as a single intravenous bolus injection or as an 8-h continuous infusion preceded by a loading dose (20% of total dosage). Mean (+/- SEM) daily urinary volume (infusion 2,860 +/- 240 ml, bolus 2,260 +/- 150 ml, p = 0.0005) and sodium excretion (infusion 210 +/- 40 mmol, bolus 150 +/- 20 mmol, p = 0.0045) were significantly higher after treatment with continuous infusion than with bolus injection, despite significantly lower urinary furosemide excretion (infusion 310 +/- 60 mg every 24 h, bolus 330 +/- 60 mg every 24 h, p = 0.0195). The maximal plasma furosemide concentration was significantly higher after bolus injection than during continuous infusion (infusion 24 +/- 5 micrograms/ml, bolus 95 +/- 20 micrograms/ml, p < 0.0001). Short-term, completely reversible hearing loss was reported only after bolus injection in 5 patients. We conclude that in patients with severe heart failure, high dose furosemide administered as a continuous infusion is more efficacious than bolus injection and causes less ototoxic side effects.

Pharmacokinetics and pharmacodynamics of furosemide after intravenous and oral administration to spontaneously hypertensive rats and DOCA‐salt‐induced hypertensive rats

The pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.), 1 mg/100 g body weight, and oral administration, 2 mg per 100 g body weight, to spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats). After i.v. administration, the 8 h urinary excretion of furosemide/g kidney (397 versus 572 micrograms) was significantly lower and the non-renal clearance (5.78 versus 3.94 ml min-1 kg-1) was significantly faster in SHRs of 16 weeks of age than in age-matched control Wistar rats. This suggested that the non-renal metabolism of furosemide could be faster in SHRs of 16 weeks of age than in age-matched control Wistar rats, and this could be supported by the significantly greater amount of 4-chloro-5-sulphamoyl anthranilic acid, a metabolite of furosemide, excreted in 8 h urine as expressed in terms of furosemide (11.1 versus 4.79% of the i.v. dose) in SHRs. It could also be supported at least in part by a study of liver homogenate; the amount of furosemide remaining per gram of liver after 30 min incubation of 50 micrograms of furosemide with the 9000g supernatant fraction of liver homogenate was significantly smaller (40.4 versus 43.7 micrograms) in SHRs of 16 weeks of age than in age-matched Wistar rats. The greater metabolic activity of furosemide in liver may also be supported by the result that the amount of hepatic cytochrome P-450 (0.7013 versus 0.5186 nmol/mg protein) and the weights of liver (3.52 versus 2.93% of body weight) were significantly greater in SHRs of 16 weeks of age than in age-matched Wistar rats. After i.v. administration of furosemide, the 8 h urine output (9.93 versus 16.5 ml) and 8 h urinary excretion of sodium (1.21 versus 2.05 mmol) and chloride (1.37 versus 2.17 mmol) per gram of kidney in SHRs of 16 weeks of age were lower than those in age-matched Wistar rats, this could be due to the significantly smaller amount of furosemide excreted in 8 h urine per gram of kidney. After oral administration, the pharmacokinetics and pharmacodynamics of furosemide were not significantly different between SHRs and the control Wistar rats of 16 weeks of age. After i.v. and oral administration of furosemide, there were no significant differences in the pharmacokinetics and pharmacodynamics between DOCA-salt rats and control SD rats of 16 weeks of age except for the significantly lower urinary excretion of potassium per gram of kidney in DOCA-salt rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Daily variation in the urinary excretion of furosemide in young and aged rats

We have recently demonstrated that the time-dependent difference in urinary excretion of furosemide, a loop diuretic, diminishes during the aging process and disappears by 18 months of age in rats. The present study was undertaken to examine whether the amplitude of the daily variations in the urinary excretion of furosemide or their pattern, or both, are influenced in aged animals. Young (3 months of age) and aged (30 months of age) Wistar rats were maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Furosemide (30 mg/kg) was given orally at 4 am, 8 am, 12 am, 4 pm, 8 pm or 12 pm. Urine was collected for 8 hours after furosemide administration and urinary excretion of furosemide was determined. There were significant daily variations in the urinary furosemide and the urine volume with the peak at 8 am and the trough at 12 pm in both groups of rats. The differences in these parameters between the 8 am and 12 pm trials were significantly smaller in the aged than in the young rats. These results suggest that the age-related alteration in the time-dependent phenomenon of furosemide is caused by the decreased amplitude of the daily variation in the urinary furosemide excretion and its diuretic effect.

Diminished diuretic and natriuretic response to furosemide in potassium-depleted rats.

Renal clearance and tubule microperfusion experiments were carried out to investigate the effects of chronic potassium depletion upon the renal response to furosemide. Rats kept on a potassium-deficient diet for 3 weeks developed hypokalemia, metabolic alkalosis, and decreased aldosterone levels. These rats responded to an oral administration of furosemide (32 mg/kg) with a blunted excretion rate of urine and sodium. Whereas furosemide increased fractional urine sodium excretion to 5.2% in control rats, the corresponding rate in potassium-depleted rats was 2.8%. The urinary excretion of furosemide was also significantly reduced during potassium depletion from 3.06 mg/kg in control rats to 0.97 mg/kg in potassium-depleted rats. In separate experiments, loops of Henle were pump-perfused with furosemide-containing solutions in control and potassium-depleted rats. No major modification of the inhibitory effects of furosemide on sodium transport was observed when the potassium concentration of the perfusion fluid was kept at the low levels expected in hypokalemic rats. Metabolic alkalosis unaccompanied by potassium deprivation did not decrease the diuretic response to furosemide. These experiments indicate that potassium deprivation reduces the diuretic effects of furosemide by mechanisms including diminished furosemide delivery to its tubule site of action.

Time-dependent change in the toxic effects of amikacin on renal functions

The present study was undertaken to examine whether there was a time-dependent change in the toxic effects of amikacin, an aminoglycoside, on renal functions. Male Wistar rats were maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Amikacin (1.2 g/kg) was injected intraperitoneally to animals at 4 am, 10 am, 4 pm or 10 pm. Glomerular function estimated by creatinine clearance (Clcr) and tubular function estimated by urinary excretion of a loop diuretic, furosemide, which was excreted in urine mainly by tubular secretion, were determined before and 24 hours after amikacin injection. The values of these parameters were reduced by amikacin at each observation point. The magnitude of these decrements was greatest at 4 pm both for Clcr and urinary furosemide excretion. These results suggest that the toxic effects of amikacin on renal glomerular and tubular functions vary with its time of administration.

The pharmacokinetics and pharmacodynamics of furosemide in the anaesthetized dog.

The correlation between pharmacokinetics and dynamics of furosemide was investigated in anaesthetized dogs. After intravenous administration (i.v.) of furosemide (5 mg/kg), the plasma concentration declined rapidly with bioexponential decay. The half-life (t1/2 beta) of the late phase of elimination was 0.931 +/- 0.187 h and the apparent volume of distribution at steady state was 0.25 +/- 0.043 l/Kg. The total clearance (Cltot) was 0.435 +/- 0.031 l/h/kg, in which the renal clearance was 0.260 +/- 0.020 (about 60% of Cltot). The change in rate of urinary excretion of furosemide was similar to the plasma concentration decay curve. The diuretic effect of furosemide was accompanied by an extreme increase in the excretion rate of sodium and chloride, but not potassium. The relationships between the diuretic response and the plasma concentration or the urinary excretion rate of furosemide was depicted by sigmoidal dose-response curves in both cases. The half-maximum effect was obtained at 1.5 micrograms/ml of plasma concentration or at 80 micrograms/min of excretion rate of furosemide.

Chronopharmacology of Furosemide in Rats with Amikacin-Induced Acute Renal Damage

To examine the influence of amikacin-induced acute renal damage on the urinary excretion of furosemide and the time-dependent variation in the urinary amount of the agent, amikacin (1.2 g/kg) was given intraperitoneally to Wistar rats. Study I: Three percent b.w. of 1% NaCl solution was given orally before and after amikacin treatment, and an 8-hour urine for N-acetyl-β-D-glucosaminidase (NAG) was collected. Study II: Furosemide (30 mg/kg) in 3% b.w. of 1% NaCl solution was given orally at 12 a.m. or 12 p.m. before and after amikacin treatment, and an 8-hour urine for sodium and furosemide was collected. Following amikacin treatment, urinary excretion of NAG increased, while urine volume and urinary excretion of sodium and furosemide decreased. Urinary excretion of furosemide and its diuretic effects were significantly greater at 12 a.m. than at 12 p.m. before and after treatment. However the time-dependent differences in these parameters were diminished by amikacin treatment. These results suggest that the urinary excretion of furosemide is reduced and the extents of the time-dependent variation in the urinary furosemide and its diuretic effects are altered in rats with amikacin-induced renal damage.

Chronopharmacology of furosemide in rats with amikacin-induced acute renal damage.

To examine the influence of amikacin-induced acute renal damage on the urinary excretion of furosemide and the time-dependent variation in the urinary amount of the agent, amikacin (1.2 g/kg) was given intraperitoneally to Wistar rats. Study I: Three percent b.w. of 1% NaCl solution was given orally before and after amikacin treatment, and an 8-hour urine for N-acetyl-beta-D-glucosaminidase (NAG) was collected. Study II: Furosemide (30 mg/kg) in 3% b.w. of 1% NaCl solution was given orally at 12 a.m. or 12 p.m. before and after amikacin treatment, and an 8-hour urine for sodium and furosemide was collected. Following amikacin treatment, urinary excretion of NAG increased, while urine volume and urinary excretion of sodium and furosemide decreased. Urinary excretion of furosemide and its diuretic effects were significantly greater at 12 a.m. than at 12 p.m. before and after treatment. However the time-dependent differences in these parameters were diminished by amikacin treatment. These results suggest that the urinary excretion of furosemide is reduced and the extents of the time-dependent variation in the urinary furosemide and its diuretic effects are altered in rats with amikacin-induced renal damage.

Urinary excretion of furosemide in rats with HgCl 2-induced acute renal damage

To examine the influence of mercuric chloride (HgCl 2)-induced acute renal damage on urinary excretion of furosemide, HgCl 2 (1 mg/kg) or its vehicle alone was given intraperitoneally to Wistar rats. The following two experiments were done. Study I: Three percent body weight (b.w.) of 1% NaCl solution or furosemide (30 mg/kg) in 3% b.w. of 1% NaCl solution was given orally before and after HgCl 2 treatment, and an 8-hour urine was collected. Study II: Furosemide (30 mg/kg) was given orally, and blood samples were obtained at 1, 2, 3, 4, 6 and 8 hours after administration. Urinary excretion of N-acetyl-β-D-glucosaminidase increased, and urine volume and urinary excretions of furosemide and sodium decreased in the HgCl 2-treated rats. There were significant correlations between the urinary furosemide and its diuretic effects. Regression lines after HgCl 2 were significantly different from those before treatment. The values of absorption as well as elimination rate constant were smaller, while the time to maximum concentration and the elimination half-life were longer in the HgCl 2-treated rats compared to vehicle-treated animals. These results suggest that the urinary excretion of furosemide and the responsiveness of renal tubular cells to this agent are impaired in rats with HgCl 2-induced acute renal damage.

Influence of renal denervation on chronopharmacology of furosemide in rats

Our previous studies have suggested that the adrenergic nervous system is involved in the mechanism responsible for the time-dependent change in the urinary excretion of furosemide in rats. To examine a potential role of renal nerves in this phenomenon, renal denervation or sham operation was performed using unilaterally nephrectomized rats. Furosemide (30 mg/kg) was given orally at 12 am or 12 pm. Urine was collected for 8 hours after furosemide dosing, and urinary excretions of furosemide and sodium were determined. Urinary furosemide excretion and diuretic effects of the agent (urine volume and urinary sodium) were significantly greater at 12 am than at 12 pm in the sham-operated group of rats. However these administration time-dependent changes in urinary furosemide and its diuretic effects disappeared in the renal-denervated group of animals. These results suggest that the renal nerves contribute to the time-dependent changes in the urinary excretion of furosemide and its subsequent diuretic effects.