Pharmacokinetic Parameters Of Furosemide Research Articles

Evaluation of renal excretion and pharmacokinetics of furosemide in rats after acute exposure to high altitude at 4300 m.

With studies indicative of altered renal excretion under high altitude-induced hypobaric hypoxia, the consideration of better therapeutic approaches has long been the aim of research on the management of high altitude related illness. The pharmacokinetics of drugs such as furosemide might be altered under hypoxic conditions, making it essential to establish different dose-regimens to maintain therapeutic efficacy or to avoid toxic side effects at high altitude. Simultaneously, drug-drug interactions (DDIs) mediated by OAT1 occur at high altitude, severely affecting furosemide pharmacokinetics. This study investigated the influence of acute exposure to high altitude at 4300m on the renal excretion of furosemide in rats. Significant changes in physiological parameters and kidney histopathology were found after acute high altitude exposure. Compared with low altitude, the pharmacokinetics of furosemide and the expression level of OAT1 in kidney were significantly changed after rapid ascent to high altitude. Additionally, the down-regulated OAT1 expression further sustained the potential mechanism for the decreased renal excretion of furosemide, resulting in extended residence of the drug in the human body. The elevation of AUC, Cmax , MRT, t1/2 of furosemide, and decreased CL at high altitude further reinforced the current findings. Moreover, the absorption of furosemide was markedly increased and renal excretion significantly declined after co-administration of captopril, resulting in local drug interaction at high altitude. In conclusion, acute exposure to high altitude may significantly affect the renal excretion of furosemide and the pharmacokinetic parameters of furosemide were altered after co-administration of captopril, which may then impact the conventional therapeutic dosage.

EFFECT OF 70% ETHANOL EXTRACT OF ORTHOSIPHONIS STAMINEUS BENTH LEAVES ON THE PHARMACOKINETIC PARAMETERS OF FUROSEMIDE IN MALE WHITE RATS

Objective: This study aimed to observe the effect of the 70% ethanol extract of Orthosiphonis stamineus Benth leaves on the pharmacokineticparameters of furosemide in white male rats.Methods: 18 Sprague–Dawley male rats were divided into three groups: The normal control group was given only 1% carboxymethyl cellulose,the furosemide group was given 7.2 mg/200 g body weight (BW) suspension of furosemide, and the combination group was given 700 mg/kg BWsuspension of the 70% ethanolic extract of O. stamineus Benth leaves for 4 days followed by a 7.2 mg/200 g BW suspension of furosemide. On the4th day of treatment, we performed orbital sinus blood sampling on the eyes of the rats and analyzed the levels of furosemide in plasma using highperformanceliquid chromatography.Results: Therefore, the results showed that the administration of the 70% ethanol extract of O. stamineus Benth leaves improves the pharmacokineticparameters of furosemide on Cpmax and the area under the curve (p<0.05).Conclusion: This study concludes that the 70% ethanol extract of O. stamineus Benth leaves improves the pharmacokinetic parameters of furosemidein white male rats.

Population pharmacokinetic modeling of furosemide in patients with hypertension and fluid overload conditions

Furosemide is a loop diuretic drug frequently indicated in hypertension and fluid overload conditions such as congestive heart failure and hepatic cirrhosis. The purpose of the study was to establish a population pharmacokinetic model for furosemide in Indian hypertensive and fluid overload patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of furosemide. A total of 188 furosemide plasma sample concentrations from 63 patients with hypertension or fluid overload conditions were collected in this study. The population pharmacokinetic model for furosemide was built using Phoenix NLME 1.3 software. The covariates included age, sex, body surface area, bodyweight, height and creatinine clearance (CRCL). The pharmacokinetic data of furosemide was adequately explained by a two-compartment linear pharmacokinetic model with first-order absorption and an absorption lag-time. The mean values of CL/F and Vd/F of furosemide in the patients were 15.054 Lh-1 and 4.419 L, respectively. Analysis of covariates showed that CRCL was significantly influencing the clearance of furosemide. The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of furosemide in Indian patients with hypertension and fluid overload conditions.

Expression of rat renal cortical OAT1 and OAT3 in response to acute biliary obstruction

Renal function in the course of obstructive jaundice has been the subject of great interest; however, little is known about the expression of renal organic anion transporters. The objective of this work was to study, in rats with acute extrahepatic cholestasis, the cortical renal expression of the organic anion transporter 1 (OAT1) and the organic anion transporter 3 (OAT3), in association with the pharmacokinetics and renal excretion of furosemide (FS). Male Wistar rats underwent bile duct ligation (BDL rats). Pair-fed sham-operated rats served as controls. All studies were carried out 21 hours after surgery. Rats were anesthetized and the pharmacokinetic parameters of FS and the renal elimination of FS were determined. Afterwards, the kidneys were excised and processed for immunoblot (basolateral membrane and renal homogenates) or immunocytochemical (light microscopic and confocal immunofluorescence microscopic analysis) techniques. The systemic and renal clearance of FS as well as the excreted and secreted load of FS increased in BDL rats. In kidneys from BDL rats, immunoblotting showed a significant increase in the abundance of both OAT1 and OAT3 in homogenates from renal cortex. In basolateral membranes from kidney cortex of BDL rats, OATI abundance was also increased and OAT3 abundance was not modified. Immunocytochemical techniques confirmed these results. In conclusion, acute obstructive jaundice is associated with an upregulation of OAT1 and OAT3, which might explain, at least in part, the increased systemic and renal elimination of FS.

Variability in derived parameters of furosemide pharmacokinetics

The pharmacokinetics of furosemide in normal man reported from a number of investigators show great discrepancies. We have evaluated the effect on derived pharmacokinetic parameters of furosemide of using different weighting factors or fewer data points to fit the same set of data to an exponential equation, or using noncompartmental analysis. Terminal half-lives of furosemide differed vastly, as did the volume of distribution, but to a lesser extent. The plasma clearance was rather consistent with the different methods used. Thus the discrepancies of the pharmacokinetics of furosemide may, in large part, be due to different methods of analysis of the data. The terminal half-life was most subject to errors of method and the plasma clearance the least.

Preliminary evaluation of furosemide–probenecid interaction in humans

The pharmacokinetics and pharmacodynamics of intravenous furosemide, 40mg, were studied in four healthy male subjects in a crossover fashion with and without probenecid pretreatment. In each study, 16 plasma and 10 urine samples were collected over 24hr. Fluid and electrolyte urinary losses were replaced orally throughout the study. Unchanged furosemide and probenecid were measured using high-pressure liquid chromatography; urinary sodium was measured by flame photometry. Although probenecid caused marked changes in the pharmacokinetic parameters of furosemide (increased area under the curve, decreased plasma and renal clearance, increased half-life, and decreased fraction excreted unchanged in the urine), there was no significant difference in its gross 8-hr natriuretic and diuretic effect. However, analysis of the time course of natriuresis showed a pattern similar to that of the urinary furosemide excretion rate, whereas the plasma concentration was poorly correlated over the entire dose-response curve.