Rats with congenital hydronephrosis show increased susceptibility to renal ischemia-reperfusion injury.

Many drug candidates have shown significant renoprotective effects in preclinical models; however, there is no clinically used effective pharmacotherapy for acute kidney injury. The failure to translate from bench to bedside could be due to misleading results from experimental animals with undetected congenital kidney defects. This study was performed to assess the effects of congenital hydronephrosis on the functional capacity of tubular renal transporters as well as kidney sensitivity to ischemia-reperfusion (I-R)-induced injury in male Wistar rats. Ultrasonography was used to distinguish healthy control rats from rats with hydronephrosis. L-carnitine or furosemide was administered, and serial blood samples were collected and analyzed to assess the effects of hydronephrosis on the pharmacokinetic parameters. Renal injury was induced by clamping the renal pedicles of both kidneys for 30 min with subsequent 24 hr reperfusion. The prevalence of hydronephrosis reached ~30%. The plasma concentrations after administration of L-carnitine or furosemide were similar in both groups. I-R induced more pronounced renal injury in the hydronephrotic rats than the control rats, which was evident by a significantly higher kidney injury molecule-1 concentration and lower creatinine concentration in the urine of the hydronephrotic rats than the control rats. After I-R, the gene expression levels of renal injury markers were significantly higher in the hydronephrotic kidneys than in the kidneys of control group animals. In conclusion, our results demonstrate that hydronephrotic kidneys are more susceptible to I-R-induced damage than healthy kidneys. Unilateral hydronephrosis does not affect the pharmacokinetics of substances secreted or absorbed in the renal tubules.

A Pilot Study of the Maternal-Fetal Pharmacokinetics of Furosemide in Plasma, Urine, and Amniotic Fluid of Hypertensive Parturient Women Under Cesarean Section.

The third trimester of pregnancy is related to physiological changes that can modify the process of absorption, distribution, metabolism, and excretion and, consequently, the efficacy and toxicity of drugs. However, little is known about furosemide pharmacokinetics and placental transfer in pregnancy. This study evaluated the maternal-fetal pharmacokinetics and distribution to amniotic fluid of furosemide in hypertensive parturient women under cesarean section. Twelve hypertensive parturient women under methyldopa (250 mg/8 h) and/or pindolol (10 mg/12 h) treatment received a 40-mg single oral dose of furosemide 1 to 10 hours before delivery by cesarean section. Blood and urine samples were collected for 12 hours after furosemide administration. At delivery, samples were obtained from maternal and umbilical cord blood (n = 8) to assess the transplacental transfer. Amniotic fluid (n = 4) was collected at the time of delivery. The following furosemide pharmacokinetic parameters were obtained as median (interquartile range): Cmax , 403 ng/mL (229 to 715 ng/mL); Tmax , 2.00 hours (1.50 to 4.83 hours); elimination half-life (t1/2 ), 2.50 hours (1.77 to 2.97 hours); AUC0-12 h , 1366 ng⋅h/mL (927 to 2531 ng⋅h/mL); AUC0-∞ , 1580 ng⋅h/mL (1270 to 2881 ng⋅h/mL); CL/F 25.3 L/h (13.8 to 31.4 L/h); CLR, 2.50 L/h (1.77 to 2.97 L/h); CLNR, 22.7 L/h (12.1 to 25.6 L/h); and Vd /F 82.8 L (34.4 to 173 L). The transplacental transfer of furosemide was 0.43 (0.10 to 0.73), and the amniotic fluid concentration was 11.0 ng/mL (5.51 to 14.6 ng/mL). From a clinical point of view, these results suggest that substrates of uridine diphosphate-glucuronosyltransferase isoenzymes such as furosemide may have increased clearance during pregnancy and could require dose adjustment in this population.

Furosemide stress test and interstitial fibrosis in kidney biopsies in chronic kidney disease.

BACKGROUND: Interstitial fibrosis (IF) on kidney biopsy is one of the most potent risk factors for kidney disease progression. The furosemide stress test (FST) is a validated tool that predicts the severity of acute kidney injury (especially at 2 h) in critically ill patients. Since furosemide is secreted through the kidney tubules, the response to FST represents the tubular secretory capacity. To our knowledge there is no data on the correlation between functional tubular capacity assessed by the FST with IF on kidney biopsies from patients with chronic kidney disease (CKD). The aim of this study was to determine the association between urine output (UO), Furosemide Excreted Mass (FEM) and IF on kidney biopsies after a FST. METHODS: This study included 84 patients who underwent kidney biopsy for clinical indications and a FST. The percentage of fibrosis was determined by morphometry technique and reviewed by a nephropathologist. All patients underwent a FST prior to the biopsy. Urine volume and urinary sodium were measured in addition to urine concentrations of furosemide at different times (2, 4 and 6 h). We used an established equation to determine the FEM. Values were expressed as mean, standard deviation or percentage and Pearson Correlation. RESULTS: The mean age of the participants was 38 years and 44% were male. The prevalence of diabetes mellitus, hypertension and diuretic use was significantly higher with more advanced degree of fibrosis. Nephrotic syndrome and acute kidney graft dysfunction were the most frequent indications for biopsy. eGFR was inversely related to the degree of fibrosis. Subjects with the highest degree of fibrosis (grade 3) showed a significant lower UO at first hour of the FST when compared to lower degrees of fibrosis (p = 0.015). Likewise, the total UO and the FEM was progressively lower with higher degrees of fibrosis. An inversely linear correlation between FEM and the degree of fibrosis (r = - 0.245, p = 0.02) was observed. CONCLUSIONS: Our findings indicate that interstitial fibrosis correlates with total urine output and FEM. Further studies are needed to determine if UO and FST could be a non-invasive tool to evaluate interstitial fibrosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02417883.

A new human pyridinium metabolite of furosemide, inhibitor of mitochondrial complex I, is a candidate inducer of neurodegeneration.

Pharmaceuticals and their by-products are increasingly a matter of concern, because of their unknown impacts on human health and ecosystems. The lack of information on these transformation products, which toxicity may exceed that of their parent molecules, makes their detection and toxicological evaluation impossible. Recently we characterized the Pyridinium of furosemide (PoF), a new transformation product of furosemide, the most widely used diuretic and an emerging pollutant. Here, we reveal PoF toxicity in SH-SY5Y cells leading to alpha-synuclein accumulation, reactive oxygen species generation, and apoptosis. We also showed that its mechanism of action is mediated through specific inhibition of striatal respiratory chain complex I, both in vitro by direct exposure of striatum mitochondria to PoF, and in vivo, in striatal mitochondria isolated from mice exposed to PoF for 7 days in drinking water and sacrificed 30 days later. Moreover, in mice, PoF induced neurodegenerative diseases hallmarks like phospho-Serine129 alpha-synuclein, tyrosine hydroxylase decrease in striatum, Tau accumulation in hippocampus. Finally, we uncovered PoF as a new metabolite of furosemide present in urine of patients treated with this drug by LC/MS. As a physiopathologically relevant neurodegeneration inducer, this new metabolite warrants further studies in the framework of public health and environment protection.

Pharmacodynamic assessment of diuretic efficacy and braking in a furosemide continuous infusion model.

INTRODUCTION: Diuretic failure is a potential life-ending event but is unpredictable and poorly understood. The objectives of this study were to evaluate pharmacodynamic markers of furosemide-induced diuresis and to investigate mechanisms of diuretic braking in dogs receiving constant rate infusion (CRI) of furosemide. ANIMALS: Six healthy male dogs. METHODS: Raw data and stored samples from one arm of a previously published study were further analyzed to mechanistically investigate causes of diuretic braking in these dogs. Urine volume was recorded hourly during a 5-h furosemide CRI. Urine and blood samples were collected hourly to measure serum and urine electrolytes, urine aldosterone, and plasma and urine furosemide. Serum electrolyte fractional excretion was calculated. Urine sodium concentration was indexed to urine potassium (uNa:uK) and urine furosemide (uNa:uFur) concentrations, plasma furosemide concentration was indexed to urine furosemide concentration (pFur:uFur), and urine aldosterone was indexed to urine creatinine (UAldo:C). Temporal change and the relationship to urine volume were evaluated for these measured and calculated variables. RESULTS: Urine volume was significantly correlated with urine electrolyte amounts and with uNa:uK. The ratio of pFur:uFur decreased during the infusion, whereas furosemide excretion was unchanged. CONCLUSIONS: There was a strong relationship between urine volume and absolute urine electrolyte excretion. Urine volume was strongly correlated to uNa:uK, giving it potential as a spot indicator of urine production during diuresis. The decrease in uNa:uK over time during the infusion is consistent with mineralocorticoid modification of urinary electrolyte excretion, supporting renin-angiotensin-aldosterone activation as a cause of diuretic braking in this model.

Effect of the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of a single dose of furosemide.

AIMS: Sacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be coadministered with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two-period, single-sequence study in healthy subjects. METHODS: All subjects (n = 28) received 40 mg oral single-dose furosemide during period 1, followed by a washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) was administered twice daily for 5 days and a single dose of 40 mg furosemide was coadministered on day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and the pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated. RESULTS: Coadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (Cmax ) [estimated geometric mean ratio (90% confidence interval): 0.50 (0.44, 0.56)], area under the plasma concentration-time curve (AUC) from time 0 to infinity [0.72 (0.67, 0.77)] and 24-h urinary excretion of furosemide [0.74 (0.69, 0.79)]. When coadministered with sacubitril/valsartan, 0-4-h, 4-8-h and 0-24-h diuresis in response to furosemide was reduced by ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 28.5%, 7% and 15%, respectively. Post hoc analysis of the pivotal phase III Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) indicated that the median furosemide dose was similar at baseline and at the end of the study in the sacubitril/valsartan group. CONCLUSIONS: Sacubitril/valsartan reduced plasma Cmax and AUC and 24-h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects.

Pharmacokinetics of furosemide administered 4 and 24 hours prior to high-speed exercise in horses.

Furosemide is a diuretic agent used commonly in racehorses to attenuate the bleeding associated with exercise-induced pulmonary hemorrhage (EIPH). The current study describes serum and urine concentrations and the pharmacokinetics of furosemide following administration at 4 and 24 hrs prior to maximal exercise. Eight exercised adult Thoroughbred horses received a single IV administration of 250 mg of furosemide at 4 and 24 hrs prior to maximal exercise on a high-speed treadmill. Blood and urine samples were collected at time 0 and at various times for up to 72 hrs and furosemide concentrations determined using liquid chromatography-tandem mass spectrometry. Serum furosemide concentrations remained above the LOQ (0.05 ng/ml) for 36 hrs in 3/8 and 1/8 horses in the 4- and 24-hrs groups, respectively. Serum concentration data were best fit by a two-compartment model. There was not a significant difference in the volume of distribution at steady-state (0.594 ± 0.178 [4 hrs] and 0.648 ± 0.147 [24 hrs] L/kg) or systemic clearance (0.541 ± 0.094 [4 hrs] and 0.617 ± 0.114 [24 hrs] L/hrs/kg) between horses that were exercised at 4- and 24 hrs postdrug administration. The mean ± SD elimination half-life was 3.12 ± 0.387 and 3.23 ± 0.407 hrs following administration at 4 and 24 hrs prior to exercise, respectively.

Reference values of renal tubular function tests are dependent on age and kidney function.

Electrolyte disorders due to tubular disorders are rare, and knowledge about validated clinical diagnostic tools such as tubular function tests is sparse. Reference values for tubular function tests are based on studies with small sample size in young healthy volunteers. Patients with tubular disorders, however, frequently are older and can have a compromised renal function. We therefore evaluated four tubular function tests in individuals with different ages and renal function. We performed furosemide, thiazide, furosemide-fludrocortisone, and desmopressin tests in healthy individuals aged 18-50 years, healthy individuals aged more than 50 years and individuals with compromised renal function. For each tubular function test we included 10 individuals per group. The responses in young healthy individuals were in line with previously reported values in literature. The maximal increase in fractional chloride excretion after furosemide was below the lower limit of young healthy individuals in 5/10 older subjects and in 2/10 patients with compromised renal function. The maximal increase in fractional chloride excretion after thiazide was below the lower limit of young healthy individuals in 6/10 older subjects and in 7/10 patients with compromised renal function. Median maximal urine osmolality after desmopressin was 1002 mosmol/kg H2O in young healthy individuals, 820 mosmol/kg H2O in older subjects and 624 mosmol/kg H2O in patients with compromised renal function. Reference values for tubular function tests obtained in young healthy adults thus cannot simply be extrapolated to older patients or patients with compromised kidney function. Larger validation studies are needed to define true reference values in these patient categories.

Determination of chloramphenicol in biological matrices by solid-phase membrane micro-tip extraction and capillary electrophoresis.

Solid-phase membrane micro-tip extraction (SPMMTE) and capillary electrophoresis (CE) methods were developed and validated for analysis of chloramphenicol in human plasma and urine samples. Iron composite nanoparticles were prepared using green technology. CE was carried out using a silica capillary (60 cm × 50 µm i.d.), phosphate buffer (50 mm, 8.0 pH)-acetonitrile (95:5, v/v) as the background electrolyte, 10 kV voltage, 280 nm detection, 20 s injection time and 27 ± 1°C temperature. Frusemide was used as an internal standard. The values of migration time, electrophoretic mobility, electrophoretic velocity and theoretical plates of chloramphenicol were 12.254 min, 4.44 × 10, 7.41 × 10 and 11,227. The limits of detection and quantitation of chloramphenicol were 0.1 and 1.0 µg/mL. Recovery of chloramphenicol in the standard solution was 95%. Solid-phase membrane micro-tip extraction and capillary electrophoresis methods may be used to analyze chloramphenicol in human plasma and urine samples of any patient.

Development and characterization of an electrochemical sensor for furosemide detection based on electropolymerized molecularly imprinted polymer.

A novel electrochemical sensor based on a molecularly imprinted polymer, poly(o-phenylenediamine) (PoPD), has been developed for selective and sensitive detection of furosemide. The sensor was prepared by incorporating of furosemide as template molecules during the electropolymerization of o-phenylenediamine on a gold electrode. To develop the molecularly imprinted polymer (MIP), the template molecules were removed from the modified electrode's surface by washing it with 0.25 mol L(-1) NaOH solution. The imprinted layer was characterized by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and atomic force microscopy (AFM). The sensor's preparation conditions including furosemide concentration, the number of CV cycles in the electropolymerization process, extraction solution of the template from the imprinted film, the incubation time and the pH level were optimized. The incubation of the MIP-modified electrode, with respect to furosemide concentration, resulted in a suppression of the K4[Fe(CN)6] oxidation process. Under the optimal experimental conditions, the response of the imprinted sensor was linear in the range of 1.0×10(-7)-7.0×10(-6) mol L(-1) of furosemide. The detection limit was obtained as 7.0×10(-8) mol L(-1) for furosemide by using this sensor. The sensor was successfully used to determine the furosemide amount in the tablet and in human urine samples with satisfactory results.

Rapid determination of furosemide in drug and blood plasma of wrestlers by a carboxyl-MWCNT sensor.

A novel method is developed for the quantification of furosemide in biological fluids. The method is based on the electro-reduction of Zn(II)-furosemide complex at carboxyl-MWCNT modified glassy carbon electrode. It is shown that, in Britton-Robinson buffer (pH5.7) the reduction peak of Zn(II)-furosemide complex formed at -1.0 V (versus, Ag/AgCl). The increment of current signal obtained from the reduction peak current of the Zn(II)-furosemide complex was rectilinear with furosemide concentration in the range of 0.03 to 140.0 µg ml(-1), with a detection limit of 0.007 µg ml(-1). The drug recovery ranged between 97.8% and 100.8% and the mean drug recovery was 98.89%. The accuracies (relative error% and RSD%) were less than 15% and are acceptable according to the US FDA guideline for bioanalytical method validation. The sensor was used for quantification of furosemide in drug and biological fluid samples. The data of drug analysis were compared with the standard method.

[Simultaneous determination of four drugs for kidney diseases in urine by high performance liquid chromatography].

A high performance liquid chromatographic (HPLC) method was proposed for the simultaneous determination of four drugs for kidney disease, enalapril, triamterene, furosemide and valsartan. After proteins being removed by acetone precipitation method, freeze drying and redissolving in mobile phase, the urine samples were analyzed by HPLC. Chromatographic separation was performed on a WondaSil C18-WR (150 mm x 4.6 mm, 5 µm) in gradient elution mode using 10.0 mmol/L ammonium acetate aqueous solution (pH 3.90) and acetonitrile as mobile phases at a flow rate of 1.0 mL/min. The detection wavelength was set at 254 nm. Under the optimized conditions, good linearities were obtained in the range of 0.15-300 mg/L, 0.05-100 mg/L, 0.75-750 mg/L, 0.05-100 mg/L, and the detection limits were 1.38 x 10(-2), 7. 67x103, 3.69x 10-2, 1. 16x 10-2 mg/L for enalapril, triamterene, furosemide and valsartan, respectively. The recoveries were in the range of 89.49%-99.20% with the relative standard deviations (RSDs) among 4.12%-9.44%. The method is simple, accurate and effective, and the results showed the method is applicable for the analysis of the four drugs for kidney diseases in real urine samples.

[Detection of plasma and urine furosemide based on online enrichment and restricted- access media coupled with high-performance liquid chromatography].

OBJECTIVE: To establish a method based on restricted access media-high performance liquid chromatography for direct online sample injection and detection of plasma and urine furosemide in rats. METHODS: The column of restricted access media was used as the pre-treatment column and a C18 column as the analytical column. The mobile phase of the pre- treatment column was water-methanol (95:5, V/V) with a volume percentage of formic acid of 0.1%. The mobile phase of the analytical column was methanol-water (65:35, V/V) for plasma and methanol-water (55:45, V/V) for urine samples, all containing a volume percentage of formic acid of 0.1% with a flow rate of 1 ml/min. The detection wavelength was 274 nm and the column temperature was maintained at 25 degrees celsius. RESULTS: The calibration curve showed an excellent linear relationship in rat plasma furosemide concentration range of 0.1-3.2 µg/ml (r=0.9995) and in urine concentration range of 0.5-32 µg/ml (r=0.9991). The average recoveries of furosemide at 3 spiked levels ranged from 101.82% to 113.36% for plasma and from 98.75% to 112.27% for urine samples. The detection showed good intra- and inter-day assay precisions and accuracies with the relative standard deviations all below 5%. The pharmacokinetic parameters AUC(0→24) was 6.265 g/(ml·h) with a t(1/2) of 2.447 h and a C(Max) of 1.414 g/ml. The mean cumulative excretory rate of furosemide in the urine of rats over 24 h was 32.50%-39.08%. CONCLUSION: Detection of furosemide in plasma and urine samples using restricted access media-high performance liquid chromatography is simple and efficient and allows direct online injection of the samples.

Perinatal growth restriction decreases diuretic action of furosemide in adult rats.

Perinatal growth restriction programs higher risk for chronic disease during adulthood via morphological and physiological changes in organ systems. Perinatal growth restriction is highly correlated with a decreased nephron number, altered renal function and subsequent hypertension. We hypothesize that such renal maladaptations result in altered pharmacologic patterns for life. Maternal protein restriction during gestation and lactation was used to induce perinatal growth restriction in the current study. The diuretic response of furosemide (2mg/kg single i.p. dose) in perinatally growth restricted rats during adulthood was investigated. Diuresis, natriuresis and renal excretion of furosemide were significantly reduced relative to controls, indicative of decreased efficacy. While a modest 12% decrease in diuresis was observed in males, females experienced 26% reduction. It is important to note that the baseline urine output and natriuresis were similar between treatment groups. The in vitro renal and hepatic metabolism of furosemide, the in vivo urinary excretion of the metabolite, and the expression of renal drug transporters were unaltered. Creatinine clearance was significantly reduced by 15% and 19% in perinatally growth restricted male and female rats, respectively. Further evidence of renal insufficiency was suggested by decreased uric acid clearance. Renal protein expression of sodium-potassium-chloride cotransporter, a pharmacodynamic target, was unaltered. In summary, perinatal growth restriction could permanently imprint pharmacokinetic processes affecting drug response.

Co-administration of furosemide with albumin for overcoming diuretic resistance in patients with hypoalbuminemia: a meta-analysis.

PURPOSE: To systematically review clinical studies of co-administration of albumin and loop diuretics in hypoalbuminemic patients as a strategy to overcome diuretic resistance. MATERIALS AND METHODS: Systematic search of electronic databases up to October 2012. We included randomized clinical trials of adults with hypoalbuminemia, comparing co-administration of loop diuretics and albumin versus loop diuretics alone. Quantitative data were synthesized with meta-analytic techniques for clinical, surrogate (urinary volume and urinary sodium excretion) and intermediate (pharmacokinetic and hemodynamic parameters) outcomes. RESULTS: Ten studies were included, of which 8 trials with crossover design were synthesized with meta-analysis. A statistically significant increase in the amount of urine volume (increment of 231 mL [95% confidence interval 135.5-326.5]) and sodium excreted (15.9 mEq [4.9-26.8]) at 8 hours were found in favor of co-administration of albumin and furosemide. These differences were no longer statistically significant at 24 hours. Meta-analyses for intermediate outcomes (ie, furosemide excretion, distribution volume etc.) did not reveal statistically significant differences. CONCLUSIONS: Synthesis of a heterogeneous body of evidence shows transient effects of modest clinical significance for co-administration of albumin with furosemide in hypoalbuminemic patients. Pragmatic, large-scale randomized studies are needed to delineate the role of this strategy.

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.

Pharmacokinetic and pharmacodynamic alterations in the Roux-en-Y gastric bypass recipients.

OBJECTIVE: We conducted a pharmacokinetic (PK) study and a pharmacodynamic (PD) study to assess whether Roux-en-Y gastric bypass (RYGB) surgery is associated with significant changes to PK and PD of oral medications. BACKGROUND: The effect of RYGB on oral drug disposition is not well understood. METHODS: An oral cocktail of probe drugs for major drug-metabolizing enzymes (caffeine, tolbutamide, omeprazole, dextromethorphan, and oral and intravenous midazolam) was administered to 18 RYGB recipients and 18 controls. Timed blood and urine samples were obtained for PK analyses. Forty mg of oral furosemide was administered to 13 RYGB recipients and 14 controls, and urine and blood samples were collected for assessing furosemidePK, and urine volume and urine sodium excretion for PD analyses. RESULTS: Compared with controls, the RYGB group had significantly lower time to maximum plasma concentration (tmax) for caffeine (0.58 ± 0.5 vs 2.1 ± 2.2 hours, P < 0.0001), tolbutamide (1.4 ± 1.8 vs 2.1 ± 2.2 hours, P = 0.0001), omeprazole (1.1 ± 1.1 vs 4.4 ± 1.3 hours, P < 0.0001), and oral midazolam (0.5 ± 0.2 vs 0.7 ± 0.4 hours, P < 0.01). However, maximum plasma concentration, half-life, area under the curve, and oral bioavailability were not different. Compared with controls, the RYGB group had brisk natriuresis, with significantly lower tmax for urine sodium (1.3 ± 0.5 vs 3.1 ± 2.3 hours, P < 0.02) and correspondingly lower tmax for furosemide (1.8 ± 0.3 vs 4.2 ± 1.2 hours, P = 0.006). However, 6-hour urine sodium and 6-hour urine volume were not different between the two groups. CONCLUSIONS: RYGB recipients have significantly shorter tmax for the studied orally administered medications, but otherwise no other significant changes in PK were reported.

Effects of furosemide and the combination of furosemide and the labeled dosage of pimobendan on the circulating renin-angiotensin-aldosterone system in clinically normal dogs.

OBJECTIVE: To evaluate the effect of administration of the labeled dosage of pimobendan to dogs with furosemide-induced activation of the renin-angiotensin-aldosterone system (RAAS). ANIMALS: 12 healthy hound-type dogs. PROCEDURES: Dogs were allocated into 2 groups (6 dogs/group). One group received furosemide (2 mg/kg, PO, q 12 h) for 10 days (days 1 to 10). The second group received a combination of furosemide (2 mg/kg, PO, q 12 h) and pimobendan (0.25 mg/kg, PO, q 12 h) for 10 days (days 1 to 10). To determine the effect of the medications on the RAAS, 2 urine samples/d were obtained for determination of the urinary aldosterone-to-creatinine ratio (A:C) on days 0 (baseline), 5, and 10. RESULTS: Mean ± SD urinary A:C increased significantly after administration of furosemide (baseline, 0.37 ± 0.14 µg/g; day 5, 0.89 ± 0.23 µg/g) or the combination of furosemide and pimobendan (baseline, 0.36 ± 0.22 µg/g; day 5, 0.88 ± 0.55 µg/g). Mean urinary A:C on day 10 was 0.95 ± 0.63 µg/g for furosemide alone and 0.85 ± 0.21 µg/g for the combination of furosemide and pimobendan. CONCLUSIONS AND CLINICAL RELEVANCE: Furosemide-induced RAAS activation appeared to plateau by day 5. Administration of pimobendan at a standard dosage did not enhance or suppress furosemide-induced RAAS activation. These results in clinically normal dogs suggested that furosemide, administered with or without pimobendan, should be accompanied by RAAS-suppressive treatment.

Rapid UHPLC method for simultaneous determination of vancomycin, terbinafine, spironolactone, furosemide and their metabolites: application to human plasma and urine.

The ultra high performance liquid chromatography (UHPLC)-UV method for the simultaneous determination of furosemide, saluamine (furosemide metabolite), spironolactone, carnenone (spironolactone active metabolite), terbinafine, N-desmethylcarboxy terbinafine (terbinafine metabolite) and vancomycin in human plasma and urine is proposed. Good separation of the analytes was achieved with the gradient RP-UHPLC-UV with the mobile phase composed as acetonitrile and 0.1% formic acid. The determined substances were eluted from a Hypersil GOLD C(18)e (50 mm x 2.1 mm, 1.7 microm particles) column in 3.3 min. Good linear relationships were observed for all of the analytes (R(2) higher than 0.994). The limit of detection (LOD) values varied from 0.01 to 0.07 microg ml(-1), with vancomycin as an exception (0.11 microg ml(-1)). After protein precipitation and solid-phase extraction, samples of plasma and urine were analyzed. Thanks to the short analysis time and small quantities of urine or plasma needed, this method can be applied to routine clinical analysis.

[Detection of selected diuretics in biological fluids by chromatography mass spectrometry].

Modified methods for the detection and measurement of furosemide and spironolactone in biological fluids has been developed based on gas chromatography mass spectrometry. Optimal conditions for chromatography are described for the determination of the diuretic agents of interest. The proposed methods were verified by analysing urine samples obtained from patients with chronic cardiac insufficiency.