Furosemide Concentrations Research Articles

Pharmacokinetics and Pharmacodynamics of Furosemide after Oral Administration to Horses

Furosemide is the most common diuretic drug used in horses. Furosemide is routinely administered as IV or IM bolus doses 3-4 times a day. Administration PO is often suggested as an alternative, even though documentation of absorption and efficacy in horses is lacking. This study was carried out in a randomized, crossover design and compared 8-hour urine volume among control horses that received placebo, horses that received furosemide at 1 mg/kg PO, and horses that received furosemide at 1 mg/kg IV. Blood samples for analysis of plasma furosemide concentrations, PCV, and total solids were obtained at specific time points from treated horses. Furosemide concentrations were determined by reversed-phase high-performance liquid chromatography with fluorescent detection. Systemic availability of furosemide PO was poor, erratic, and variable among horses. Median systemic bioavailability was 5.4% (25th percentile, 75th percentile: 3.5, 9.6). Horses that received furosemide IV produced 7.4 L (7.1, 7.7) of urine over the 8-hour period. The maximum plasma concentration of 0.03 microg/mL after administration PO was not sufficient to increase urine volume compared with control horses (1.2 L [1.0, 1.4] PO versus 1.2 L [1.0, 1.4] control). There was a mild decrease in urine specific gravity within 1-2 hours after administration of furosemide PO, and urine specific gravity was significantly lower in horses treated with furosemide PO compared with control horses at the 2-hour time point. Systemic availability of furosemide PO was poor and variable. Furosemide at 1 mg/kg PO did not induce diuresis in horses.

Statistical evaluation of the regulatory guidelines for use of furosemide in race horses.

The pharmacokinetic behavior of furosemide concentrations in performance horses is of great interest to the equine industry and equine researchers. Specifically, such information is useful for the evaluation of the existing guidelines in several racing jurisdictions and for the possible development of new guidelines for varying time periods after administration. We studied several approaches within the framework of nonlinear mixed effects models to increase the accuracy of evaluating these guidelines. Theoretical properties of the proposed methods were examined and the variances of the resulting estimators compared. Their numerical performances were further evaluated through simulations. Finally, we applied these methods to a furosemide concentration profile data set and used our findings to address certain important practical issues.

Plasma pharmacokinetics of intravenous and intramuscular furosemide in the camel ( Camelus dromedarius)

Single bolus intravenous (i.v.) and intramuscular (i.m.) doses of furosemide (1·5 mg kg −1) were administered in a crossover design to three female and three male adult, dromedary camels. Plasma furosemide concentrations were assayed by HPLC and sodium, potassium and chloride concentrations were measured using ion-selective electrodes. Plasma furosemide concentration-time plots indicated multi-compartment disposition, and there was considerable intersubject variability in the pharmacokinetic parameters. The mean (SD) i.v. terminal elimination half-life was 118 (67) minutes. The systemic clearance was 5·4 (1·2) ml min −1 kg −1, and the steady-state volume of distribution was 0·43 (0·14) litre kg −1. The mean absorption time after i.m. dosing was 33 (62) minutes, while the absolute bioavailability was 71 (20) per cent. The glucuronide metabolite of furosemide was not detected in plasma. Clearance was lower, volume of distribution was larger, and half-life was longer compared with published data for dogs, horses, rats and humans. Plasma potassium and sodium concentrations were significantly diminished (P<0·05) by an average of 35·6 per cent (two to six hours post-dose) and 11·3 per cent (eight hours post-dose), respectively. Plasma chloride concentrations were not significantly affected by furosemide administration.

CAMP dependence of Ca2+ entry during agonist-induced contractions of the uterine smooth muscles

Possible involvement of cAMP-dependent mechanisms in the development of both phasic and tonic contractions induced by oxytocin — OT (25 nM and 25 µM, respectively), as well as of KCl-induced contracture, was studied on the myometrium of estradiol-dominated rats using the myometrial strips with suppressed spontaneous mechanical activity. The intracellular cAMP level was modulated by furosemide that had been previously shown to decrease cAMP content in the rat myometrium tissue. When added to the medium in the pulse mode together with 25 nM OT, furosemide (0.02 mM) increased contraction amplitude by 224%, whereas higher, 0.2 and 20 mM, furosemide concentrations suppressed the response by 286% or totally removed it, respectively. Being present in the bath permanently, 0.2 mM furosemide progressively decreased the amplitude of OT-induced phasic contractions. Under such conditions, 0.02 mM furosemide exerted biphasic effect on the responses, so that the initial enhancement was replaced by the progressive inhibition. Dibutyryl-cAMP (dbcAMP) at a proper concentration restored the responsiveness of the tissue to OT in the presence of furosemide in the saturating concentration. Contractile responses induced by 25 µM OT comprised both phasic and tonic components. In a Ca2+-free medium, the OT-induced contractions seemed to be associated with Ca2+ release from intracellular stores. Permanent presence of furosemide in the CaCl2-containing medium inhibited OT-induced responses in the same manner as omission of Ca2+ from the medium, i.e., furosemide did not affect the responses caused by Ca2+ release but inhibited those mediated via acceleration of the Ca2+ influx. The furosemide-sensitive component of responses to OT was combined with a persistent contraction caused by KCl depolarization; there was a moderate decrease in amplitude of the KCl-induced contracture due to furosemide action. The decrease could be prevented by dbcAMP addition. It is suggested that both voltage-gated and receptor-operated Ca2+ entries induced by OT are regulated by cAMP-dependent protein kinases, while Ca2+ extrusion into the extracellular space does not depend on the intracellular cAMP.

Monitoring furosemide in racehorses participating in an EIPH program

Analytical procedures were developed to monitor furosemide concentrations in post-race serum and urine samples obtained from horses participating in an exercise-induced pulmonary haemorrhage (EIPH) program. High performance liquid chromatography with ultraviolet light detection proved a reliable, sensitive method for measuring urinary furosemide concentrations up to 12 h after administration of either 150 or 250 mg of the drug to race horses. However, this method was unreliable for determination of serum furosemide concentration. High performance liquid chromatography with fluorescence detection proved a reliable, sensitive method for measuring serum furosemide concentration in horses administered 250 mg of the diuretic, permitting detection of approximately 5-10 ng/ml 6 h after treatment. This method was applied to field conditions where furosemide was administered to horses (between 150 and 250 mg intravenously) 4 h prior to the race. Analytical results assisted in establishing a threshold concentration of 85 ng/ml for serum furosemide. It was found that serum furosemide concentrations are a valid measure of compliance with furosemide administration in the EIPH program.

Acute respiratory acidosis: large-dose furosemide and cerebrospinal fluid ions

NaCl cotransport carrier is known to be involved in transepithelial fluid absorption and secretion in various tissues. Recent studies indicate that Na-K-2Cl cotransport carrier also exists in the choroid plexus cells and that inhibition of the carrier decreases cerebrospinal fluid (CSF) production. In this study, we used large-dose intravenous furosemide, an inhibitor of Na-K-2Cl carrier, to determine the effects on cisternal CSF ionic composition in acute respiratory acidosis. In pentobarbital-anesthetized mechanically ventilated dogs, renal pedicles were ligated to prevent furosemide-induced diuresis. The experimental group (group II, n = 7) received 400 mg/kg of furosemide intravenously, and group I (control group, n = 7) received the vehicle. In group II, serial serum and CSF furosemide concentrations were approximately 10(-3) and 10(-5) mol/l, respectively. During 5 h of acute respiratory acidosis in both groups, the mean arterial PCO2 increased approximately 25 Torr, with comparable changes in CSF PCO2. In both groups, CSF [HCO3-] and [H+] rose approximately 3 meq/l and 20 neq/l, respectively. Changes in CSF [Na+], [K+], [Cl-], and [Na(+)-Cl-] were also similar and were not significantly different from each other when the two groups were compared. These data show that furosemide at the dose that inhibits NaCl cotransport carrier does not significantly alter ionic composition of cisternal CSF.

Mechanism of electrically silent Na and Cl transport across the rumen epithelium of sheep

This study was designed to study the mechanism of electroneutral Na and Cl transport across the isolated rumen epithelium of sheep. Net sodium transport (5.75 +/- 0.35 microequiv cm-2 h-1) was significantly higher than the short-circuit current (0.95 +/- 0.08 microequiv cm-2 h-1). Both, net sodium and net chloride transport were markedly reduced by replacement of chloride, bicarbonate and sodium, respectively, but were not changed by the absence of mucosal potassium. Net sodium and net chloride absorption was significantly decreased by 1.0 mM-amiloride. Mucosal addition of bumetanide, furosemide, hydrochlorothiazide or low concentrations of amiloride (less than 0.1 mM) did not change sodium fluxes. These results provide compelling evidence consistent with the presence of Na-H exchange as the predominant electroneutral mechanism for transepithelial sodium movement. The ion replacement studies and data from literature suggest that the Na-H exchange is working in parallel with a Cl-HCO3 exchange although luminal addition of DIDS (4,4'diisothiocyanatostilbene-2,2'-disulphonate, 1 mM) did not significantly influence Cl transport.

Evaluation of high performance liquid chromatography (HPLC), enzyme linked immunosorbent assay (ELISA) and particle concentration fluorescence immunoassay (PCFIA) methods for the screening, quantitation and pharmacokinetic study of furosemide in horses

Equine plasma and urine samples were analyzed by using a high-performance liquid chromatography (HPLC), enzyme-linked immunosorbent assay (ELISA) and particle concentration fluorescence assay (PCFIA). Although ELISA and PCFIA were rapid, simple and sensitive for the screening of furosemide, they did not give reproducible quantitative results. The HPLC method, which required relatively longer analysis time, provided simple and reproducible quantitative analysis of furosemide in plasma and urine. The performance of the three methods was compared for the quantitation of furosemide in plasma obtained from thoroughbred mares dosed intravenously with furosemide (500 μg/kg ( n = 7) and 1.0 mg/kg ( n = 5)). Although the plasma furosemide profiles determined by ELISA, PCFIA and HPLC were similar, ELISA and PCFIA methods exhibited considerable variation in values. At high furosemide concentrations, the PCFIA method gave better quantitative values than ELISA. However, at trace furosemide concentrations the PCFIA method gave false positive values which were not confirmed by HPLC or ELISA. The pharmacokinetic values obtained from the HPLC data and the pharmacokinetic values obtained previously from the gas chromatographic data [4,7] were comparable. The data obtained by ELISA and PCFIA were not suitable for the pharmacokinetic calculations.

Furosemide (Frusemide)

Furosemide (frusemide) is a potent loop diuretic used in the treatment of oedematous states associated with cardiac, renal and hepatic failure, and for the treatment of hypertension. Therapy is frequently complicated by apparently erratic systemic availability from the oral route and from unpredictable responses to a given dosage. The exact mechanism of action is not fully understood, but furosemide is believed to act at the luminal surface of the ascending limb of the loop of Henle by inhibiting the active reabsorption of chloride. The response to a given dosage is modulated by the fluid and electrolyte balance of the individual. Acute and delayed tolerance has been demonstrated both in animals and in man, and is postulated to be due to the intervention of homeostatic mechanisms influencing fluid and electrolyte balances. Furosemide is delivered to its site of action by active secretion via the nonspecific organic acid pump. Comparisons between the observed diuresis/saluresis and plasma furosemide concentrations, urinary excretion rates and renal clearance found either negative or no correlations with plasma drug concentration but significant correlations with urine measurements. Response is related to the concentration of the drug in urine rather than in plasma. The most common adverse reactions attributable to furosemide therapy are essentially extensions of the therapeutic effects (i.e. fluid and electrolyte disturbances). The pharmacokinetic behaviour of furosemide is marked by a large degree of variability, derived from differences within and between both subjects and study protocols. Part of this variability can be attributed to differences in organ function, which is important in view of the types of patients treated with furosemide. On the other hand, a large proportion remains as inter- and intrasubject variation. The bioavailability of furosemide from oral dosage forms is highly variable. The poor bioavailability has been hypothesized to be due to the poor solubility of the compound, site-specific absorption, presystemic metabolism and/or other unknown mechanisms. Furosemide is highly bound to plasma proteins, almost exclusively to albumin. Although the drug is insoluble in water and favours partitioning into fatty tissue, the high degree of plasma protein binding restricts the apparent volume of distribution at steady-state to values within a multiple of 2 to 5 times the plasma volume. Furosemide has two documented metabolites--furosemide glucuronide and saluamine (CSA). The first is an accepted metabolic product, whereas the status of CSA as a metabolite is highly controversial.(ABSTRACT TRUNCATED AT 400 WORDS)

The time-course of furosemide-induced strial changes in guinea pigs after pretreatment with daltroban

It was shown previously (Ernst et al., 1989) that pretreatment of guinea pigs with a thromboxane (TX) receptor antagonist attenuates the decline of the endocochlear potential (EP) induced by furosemide. The present paper is aimed at investigating a possible correlation between the electrophysiological data and ultrastructural changes of the stria vascularis by electron microscopy. The dosages of 40, 60, and 80 mg/kg furosemide were injected after the pretreatment with the TX receptor antagonist daltroban and compared to controls which were injected with furosemide only. It was found at all furosemide concentrations that the strial changes 10 min after injection were nearly unchanged against controls. 30 min after furosemide injection, the most pronounced changes were seen when pretreating the animals: a clear reduction of the marginal cell swelling and edema in general were observed at 40 and 60 mg/kg furosemide. The guinea pigs injected with 80 mg/kg furosemide after pretreatment displayed nearly the same changes as controls.

Obesity as a risk factor in drug-induced organ injury: III. Increased liver and kidney injury by furosemide in the obese overfed rat

Effects of the diuretic drug furosemide were examined in obese animals to evaluate the hypothesis that organ damage by reactive drug metabolites may be potentiated by this disease. Obese overfed Sprague-Dawley rats that were treated ip with 450 mg/kg furosemide on the basis of total body mass suffered a 58% mortality rate over 24 h. This contrasted with 0% mortality in animals of normal body mass. On the basis of median histopathology scores, organ necrosis was judged to be greater in the liver (2+) and kidneys (1+) of obese rats than in the liver (1+) and kidneys (<1+) of normal controls ( p<0.05). Obese animals demonstrated a fourfold rise in fat mass over controls. The low solubility of furosemide in lipid makes it probable that aggravated drug toxicity in obese rats dosed to total body mass resulted in part from elevated furosemide concentrations in lean body mass. In a subsequent study designed to minimize this possibility, furosemide was administered on the basis of fat-free body mass to equalize initial drug exposure in obese and control rats. Even with this downward dosage adjustment, obese animals suffered increased hepatic necrosis (median score of 2+ versus 0 in treated controls), greater impairment of renal function (plasma creatinine concentration of 2.41 mg/dl versus 0.96 mg/dl in treated controls), and more extensive enzymuria (enzyme excretion 175–300% more elevated than in treated controls). In conclusion, obese rats appear to be at increased risk of furosemide-induced liver and kidney injury due to at least two factors: (1) increased exposure of target organs in lean body mass to furosemide when the dosing of this poorly lipophilic drug was based on total body mass, and (2) increased susceptibility of target organs in lean body mass to furosemide injury when dosing was adjusted downward to reflect fat-free body mass and to equalize initial drug exposure.

Interactive mixing between agglomerated drug particles and coarse carrier particles

AbstractThe equation of Egermann1 was used to calculate the theoretical coefficient of variation in drug content of completely random interactive mixtures containing furosemide and sodium chloride. These coefficients of variation (CV) were compared to that obtained experimentally. Although no free furosemide agglomerates or aggregates were present in the mixtures, the experimental values were consistently higher. This could only be explained if small furosemide aggregates accumulated in clefts and crevices in the sodium chloride particle surfaces. For the system examined random interactive mixtures were produced with furosemide concentrations between 0.05 and 4%

A controlled-release matrix tablet of furosemide: design, in vitro evaluation, pharmacological and pharmacodynamic evaluation

Microporous polypropylene powder (Accurel) was used for the formulation of a matrix tablet of furosemide. The formulation of the matrix tablet was based on known absorption data of furosemide in the literature. Six male volunteers participated in an in-vivo study, in which they received a 60 mg matrix tablet, a 60 mg oral solution and an i.v. bolus injection of 40 mg furosemide. The bioavailability of furosemide calculated from the AUCs and from numerical deconvolution was resp. 76.6 ± 14.9 and 73.8 ± 17.5% (P < 0.05) for the oral solution and 40.0 ± 17.8 and 37.9 ± 19.4% (P < 0.05) for the matrix tablet. Peak diuretic effects were similar to the effects of a regular furosemide tablet. The high diuretic efficacy of the matrix tablet is remarkable (compared to the oral solution and the i.v. injection) although the bioavailability is relatively low. The possibility of controlled-release dosing for furosemide has been discussed from a pharmacological point of view. The pharmacodynamic response was studied in relation to the furosemide concentrations in the urine.

Effects of Hyposmotic Shock on Ion Fluxes in Isolated Trout Hepatocytes

Isolated trout hepatocytes exposed to hypotonic Hank's medium (isotonicity x 0.70) swelled to 1.17 times the control volume after 3 min; by 15 min the cell volume had returned to normal. The ouabain-insensitive K+ uptake increased, indicating an immediate rise in K+ membrane permeability. As indicated by analysis of cellular contents, the regulatory volume decrease (RVD) was ensured by a release of intracellular K+. Na+ was not implicated in this mechanism. This potassium permeability induced by hypotonic shock was transient (maximum at 6 min), insensitive to blocking agents of voltage- and Ca2+-dependent K+ channels, and chloride-dependent. This result, together with a time-course of Cl- uptake similar to that of K+, suggests a K+/Cl- cotransport mechanism. This cotransport is inhibited by high furosemide concentrations (10(-3) mol l-1) but not by bumetanide (10(-4) mol l-1) or piretanide (10(-4) mol l-1).

Compatibility of Medications with Enteral Feedings

Administration of medications to patients with nasogastric tubes has traditionally been done in a bolus fashion. An alternative to this would be to mix the medications in the continuous drip enteral feeding with subsequent continuous administration. The purpose of this study was to determine the compatibility of select medications with Ensure, Ensure Plus, and Osmolite. We observed neither visible abnormalities in the mixtures nor change in pH of the enteral products after the addition of digoxin, theophylline, phenytoin, methyldopa, or furosemide. The addition of theophylline to all three enteral products caused a substantial increase in the osmolality. We also examined the concentrations of the mixtures to detect any changes occurring over the 12-hr infusion time. A wide variation in concentrations after the addition of phenytoin suspension was corrected by adding the injectable form to the enteral products. Digoxin and furosemide concentrations were essentially unchanged; however, the methyldopa concentration decreased up to 23% over the 12-hr study period. We, therefore, cannot recommend the addition of theophylline, phenytoin suspension, or methyldopa to the three enteral products tested. (Journal of Parenteral and Enteral Nutrition 11:183–186, 1987)

Compatibility of Medications with Enteral Feedings

Administration of medications to patients with nasogastric tubes has traditionally been done in a bolus fashion. An alternative to this would be to mix the medications in the continuous drip enteral feeding with subsequent continuous administration. The purpose of this study was to determine the compatibility of select medications with Ensure, Ensure Plus, and Osmolite. We observed neither visible abnormalities in the mixtures nor change in pH of the enteral products after the addition of digoxin, theophylline, phenytoin, methyldopa, or furosemide. The addition of theophylline to all three enteral products caused a substantial increase in the osmolality. We also examined the concentrations of the mixtures to detect any changes occurring over the 12-hr infusion time. A wide variation in concentrations after the addition of phenytoin suspension was corrected by adding the injectable form to the enteral products. Digoxin and furosemide concentrations were essentially unchanged; however, the methyldopa concentration decreased up to 23% over the 12-hr study period. We, therefore, cannot recommend the addition of theophylline, phenytoin suspension, or methyldopa to the three enteral products tested.

Inhibitory action of furosemide on the active chloride transport of papillary heart muscle in rabbit

The action of furosemide on the intracellular chloride activity, a i(Cl), of rabbit papillary muscle was investigated with Cl ion selective microelectrodes. With furosemide concentrations greater than 1 μM, a i(Cl) decreased. Furthermore, the decrease in a i(Cl) was larger as the furosenide concentration increased. Lowering the extracellular sodium concentration, [Na] o, by replacing Na with choline, significantly reduced the effect of furosemide on a i(Cl). The results provide evidence that the membrane of rabbit heart cells possess a furosemide sensitive chloride transport mechanism related to [Na] o.

Comparative Bioavailability of Two Furosemide Formulations in Humans

Twelve healthy male volunteers participated in a balanced crossover comparison of a brand-name and generic furosemide formulations. Each treatment was given as a single 40-mg tablet following an overnight fast. Furosemide concentrations in plasma and urine were determined up to 24h after treatment; urine output and urinary sodium excretion were also measured. In comparison with the brand-name tablets, generic furosemide was significantly less bioavailable. Using a 95% confidence interval approach, generic furosemide gave up to 66% lower maximum furosemide plasma levels, up to 52% less area under the plasma level curve to infinite time, and up to 37% less urinary recovery of furosemide. Comparison of the effect of the two treatments was a less sensitive measurement of bioequivalence. Confidence intervals for differeences in urinary output and sodium excretion over the period of maximum effect (0–4 h) were, however, asymmetrical, and pharmacodynamic differences between treatments were significant at the 10% level.

Plasma protein binding of furosemide in kidney transplant patients.

The present investigation was undertaken in order to determine the in vivo plasma protein binding of furosemide in kidney transplant patients and its possible consequence on furosemide effect. Using an equilibrium dialysis technique, serial plasma samples of furosemide taken after intravenous administration were dialyzed against an equal volume of isotonic Krebs Ringer bicarbonate buffer (pH 7.4). Dialysis was performed at 37 degrees C for 5 hr, and furosemide concentrations (total as well as free) were analyzed by HPLC using fluorescence detection. It was observed that kidney transplant patients on concomitant sulfisoxazole treatment (KT+) had a significantly greater value for percent free of furosemide as compared to transplant patients not on sulfisoxazole (KT-) (4.4 +/- 0.8 for KT+ vs. 1.7 +/- 0.3% for KT-; p less than 0.01) as well as to healthy volunteers (4.4 +/- 0.8 for KT+ vs. 1.2 +/- 0.2% for controls; p less than 0.01). In addition, kidney transplant patients not on concomitant sulfisoxazole treatment had a significantly higher value for percent free of furosemide with respect to healthy volunteers (p less than 0.05). Nonlinear plasma protein binding was also observed for one patient, who had values for percent free of furosemide ranging from 1.3 to 12.9%. However, no significant correlation was found between the fraction of the dose excreted unchanged in the urine and percent free of furosemide.

Effect of furosemide on the in vitro prostaglandin biosynthesis in human platelets

Effect of furosemide at various concentrations (0.05 – 4 mM) was examined on the in vitro biosynthesis of prostaglandins in human platelets. At lower furosemide concentrations (0.05 and 0.1 mM) no effect was observed. At 1 and 2 mM concentrations, PGE significantly (P < 0.01) increased. At 3 and 4 mM concentrations PGE 2 increased though not significantly probably because of the small number of samples (n=5). A decrease in PGD formation was noted at 1–4 mM furosemide concentrations, though significantly only at 3 mM conc. At 1 and 2 mM concentrations, TxB 2 and HHT increased whereas at 3 and 4 mM concentrations these metabolites were decreased. These effects were, however, not significant. No effect was observed on endoperoxide generation at 1 and 2 mM conc. Furosemide at 1 and 2 mM concentrations inhibited ADP- and arachidonic acid induced platelet aggregation. An increased platelet formation of PGE in the presence of furosemide may point to the fact that this drug shows its effect mainly, on the formation of PGE which has been found to exert a profound effect on renal blood flow and thus ameliorates some forms of hypertension.