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The effects of fatty acids, including oleate, on the interaction between furosemide and valproic acid in sera at respective serum therapeutic concentration levels were investigated using an ultrafiltration technique. The free fraction of furosemide was significantly increased in the presence of valproic acid. Mutual displacement experiments indicated that furosemide and valproic acid share a common high affinity binding site on human serum albumin (HSA). The serum free fraction of furosemide was increased by the presence of six or more fatty acid molecules per HSA molecule. This fatty acid-induced increase in the unbound fraction of furosemide was further increased by the binding of valproic acid. However, the inhibition of furosemide binding to serum for a fatty acid-valproic acid-furosemide system is nearly the same as the additive effect of fatty acid and valproic acid on the furosemide to serum. Thus, the mechanism for the displacement of HSA-bound furosemide by valproic acid was concluded to be different from that for fatty acid-catalyzed displacement.

Two kinds of dosage forms (tablets and retarded capsules) of furosemide (F) were compared in vitro dissolution profile and in vivo absorption studies. The dissolution of F from retarded capsules was extremely restricted in the first fluid of the JP XII disintegration test (within 0.8%), while the dissolution of F from tablets and retarded capsules in the second fluid of JP XII disintegration test were both complete. Metabolite specific assay of F showed F, conjugation of F with glucuronic acid (FG) and acyl migration isomers of FG (FG-iso) in urine or plasma. The mean cumulative urinary excretion of F following administration of the tablets during 24 h was twice that of retarded capsules. The mean area under the plasma concentration-time curve (AUC) of F following administration of tablets was 1.5 times that of retarded capsules. The mean cumulative urine volume during 24 h, however, was not significantly different between the two dosage forms. Clockwise hysteresis relationships between the diuretic response and the urinary excretion rate of F was observed after administration of retarded capsules. A straight relation between logarithm of the diuresis and logarithm of the urinary excretion of F was observed after maximum excretion rate of F following administration of both dosage forms.

Hydroxypropylcellulose (HPC)-ethylcellulose (EC) microcapsules containing piretanide prepared by a solvent evaporation technique, were evaluated on pharmacokinetic, pharmacodynamic and pharmacological parameters in spontaneously hypertensive rats (SHR). HPC-EC10 (5:3) microcapsules showed sustained plasma piretanide levels and almost the same AUC (area under the curve) as compared with piretanide solution. Effect of treatment with the microcapsules (single oral administration per day in doses of 10 and 30 mg/kg) and the solution (double oral administration per day in doses of 5 and 15 mg/kg) was examined for 4 weeks on urine volume and urinary electrolytes excretion and blood pressure. The microcapsules and solution induced dose-dependent diuresis throughout the experimental period and a reduction in blood pressure from 2 weeks of the treatment. HPC-EC10 (5:3) microcapsules containing piretanide were satisfactory as a sustained-release preparation in the light of the anti hypertensive effect even at a half frequency of daily dosing of the solution.

The distribution of three sulfonylureas and six diuretics in rabbit erythrocytes was studied in vitro at 37 degrees C. The drugs were taken up by the erythrocyte compartment, and distribution equilibrium was reached within 60 min of incubation. A distribution percentage in erythrocyte compartment was maintained at roughly constant value over the whole concentration range of drugs. Therefore, a linear relationship was established between total concentrations of drug in whole blood or erythrocyte suspension and in the erythrocyte compartment. Bovine serum albumin combined with the erythrocyte suspension appeared to reduce drug distribution in the erythrocyte compartment. Whole blood obtained from renal failure rabbits showed greater distribution of drug in the erythrocyte compartment compared with the whole blood of a normal rabbit. This might be due to a change in plasma protein binding ability related to the progress of renal failure.

The binding of three loop diuretics, piretanide, bumetanide and furosemide, to serum proteins from patients with liver cirrhosis or fulminant hepatitis was investigated using equilibrium dialysis. A good correlation was found between serum albumin concentration and the percentage of each unbound (free) loop diuretic in patients with liver disease. The binding data obtained from patients with liver cirrhosis was compared with that of patients with chronic renal failure. Calculations made according to the Sandberg-Rosenthal's formula revealed that the maximum binding concentration (nP) varied in some cases. These findings necessitated a detailed investigation into whether the increased percentage of each unbound loop diuretic in patients with liver disease is attributable not only to lowered serum albumin concentration but also to inhibition of the protein binding by some endogenous substances. Thus, similar experiments were performed using rats with experimental liver cirrhosis. The binding of the loop diuretics to serum proteins in cirrhotic rats differed greatly from the findings obtained from cirrhotic patients. The percentage of unbound loop diuretic was well correlated with serum albumin concentration but not with the concentration of serum bilirubin (an endogenous substance) in cirrhotic rats.