Furosemide binding to human albumin and plasma of nephrotic children

Abstract

The extent and nature of furosemide (F) binding to human albumin (HA) and to the plasma of 6 children with nephrotic syndrome were studied by equilibrium dialysis at 37 degrees C and pH 7.4 with 14C-F. At a total concentration of 3.4 mug/ml (therapeutic range), the unbound fraction of F to 4 gm per 100 ml HA was 2.79 plus or minus 0.35. The degree of binding was relatively constant from 1.8 to 36 mug/ml of F concentration. The percentage of unbound F doubled when total concentration of the drug was increased more than 130 times (1.8 to 245 mug/ml). F has two classes of binding sites (n1 = 1.42, k1 = 5.07 times 10-4 M-minus 1; n2 = 3.4, k2 = 1.58 times 10-4 M-minus 1); interaction with HA involves hydrophobic, ionic, and hydrogen forces. Acetylsalicylic acid (ASA), acetazolamide, diazoxide, phenylbutazone, sulfisoxazole (S), and tolbutamide (T) decreased F binding. Combinations of ASA, S, and T exerted a strong additive displacing effect. The binding of the F metabolite (4-chloro-5-sulfamoylanthranilic acid, CSA) was studied at 1.3 and 2.6 mug/ml. The unbound fraction was 5 times that of F. CSA did not influence F binding. Studies with plasma of 7 healthy adults showed that albumin is the only plasma protein responsible for F binding. The plasma albumin concentration range of the children with nephrotic syndrome was 0.6 to 2.1 gm per 100 ml. There was some correlation between albumin concentration and binding of F (2.8 to 9.6% unbound); this corresponded with findings with HA. Albumin concentrations lower than 2 gm per 100 ml seemed to influence the extent of the unbound fraction of F considerably.

Plasma protein binding of furosemide in kidney transplant patients

“…This was probably due to the presence of endogenous and exogenous (drugs) substances which compete with furosemide for binding sites on the plasma proteins. Since furosemide is exclusively bound to albumin (7,10), the presence of hypoalbuminemia has been postulated (11) as a possible cause for reduced drug binding of furosemide in patients with renal dysfunction. However, the kidney transplant patients in this study were normal with respect to serum albumin levels, and no significant correlation was observed between percent free of furosemide and albumin concentration (Fig.…”

“…It is highly bound to plasma proteins (6)(7)(8)(9)(10)(11)(12) and gains access to its site of action in the kidney lumen primarily through active secretion via the nonspecific organic acid secretory pathway (13)(14)(15). Previous studies have shown that renal disease can effect dramatic changes in the pharmacokinetics of furosemide (6,11,(16)(17)(18)(19)(20), including impaired plasma protein binding in uremics (7,11), nephrotics (10,11), and anephric patients (6). The degree of binding of furosemide to plasma proteins in kidney transplant patients has not been reported.…”

Determinants of Urinary Output Response to IV Furosemide in Acute Kidney Injury: A Pharmacokinetic/Pharmacodynamic Study

“…Furosemide is a highly protein-bound (>98%), weak organic acid which is actively secreted into the urine by organic acid transporters (OATs) in the proximal tubules (24,25). In patients with elevated plasma urea and creatinine concentrations, uremic acids may theoretically alter furosemide PK by competing for tubular secretion by OATs (26).…”

Animal Pharmacokinetics and Interspecies Scaling of Sordarin Derivatives following Intravenous Administration

“…The dialysis chambers (Cellusep; Spectrum) have a volume of 250 l and are separated by a membrane measuring 1 cm 2 . Serum samples were dialyzed against the same volume of red blood cell buffer (20) placed in the second compartment. The chamber was then placed in a rotator (Dianorm, Munich, Germany), and dialysis was carried out at 16 rpm at 37°C for 24 h. Following incubation, aliquots of both compartments were counted, and the free fraction was calculated.…”