Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome.

Response to loop diuretics in patients with nephrotic syndrome (NS) is subnormal. Studies in animal models of NS have suggested that binding of diuretic to urinary albumin is one of the mechanisms that may be operative in this diuretic resistance. To explore this hypothesis, 12 patients with NS were studied to determine whether displacement from urinary protein binding with sulfisoxazole would restore response to 120 mg of furosemide. The study was stopped after treating seven patients because it was clear that sulfizoxazole had no effect. Sodium excretion (mean +/- SD) from furosemide alone was 239 +/- 90 versus 240 +/- 115 mEq/8 h with sulfisoxazole. Sulfisoxazole had modest effects on serum pharmacokinetics of furosemide but had no effect on either the time course of furosemide urinary excretion or overall amount excreted: 49 +/- 15 mg versus 54 +/- 12 mg for furosemide alone and furosemide plus sulfisoxazole, respectively. It is concluded that urinary protein binding of loop diuretics is not a major mechanism for the diuretic resistance of NS. In turn, strategies aimed at displacing such binding are unlikely to be clinically helpful.

Sulfadiazine versus sulfafurazole excretion in urine and risk of crystallization in children with conventional dosage regimen.

The excretion of sulfadiazine (Adiazin) (n = 8) and sulfafurazole (n = 8) in urine and the risk of crystallization were compared in children, 3-14 years of age. They suffered from acute urinary tract infection and were treated with conventional dosage regimen of either of the sulfonamides. Sulfadiazine (4 mg/kg twice daily, the initial dose 8 mg/kg) produced active serum drug levels which in relation to antimicrobial activity of sulphonamides corresponded to 25-30% of those obtained with sulfafurazole (50 mg/kg four times a day). In urine the corresponding sulfadiazine levels were 21-61% of those of sulfafurazole. In none of the urine fractions sulfadiazine concentrations exceeded the theoretical drug solubility but sulfafurazole exceeded this risk limit altogether in 4 urine fractions (2 patients). Urine sediment showed, however, sulfonamide crystals in only one urine fraction of the sulfafurazole group. The results suggest that with conventional dosage regimen sulfafurazole produces higher effective serum and urine drug concentrations in children than sulfadiazine but shows a higher risk to crystallize in urine.

Urine concentrations of chloramphenicol, tetracycline, and sulfisoxazole after oral administration to healthy adult dogs.

Chloramphenicol, tetracycline, and sulfisoxazole were administered (orally) in separate trials to clinically healthy adult dogs of both sexes at 8-hour intervals for five consecutive 8-hour test periods. All urine was collected from each dog during each test period and an aliquot from each period was assayed for antimicrobial activity. Daily doses of the antimicrobics were as follows: chloramphenicol 99 mg/kg of body weight, tetracycline 55 mg/kg, and sulfisoxazole 66 mg/kg. Mean 8-hour urine concentrations (+/- 1SD) for chloramphenicol were 124 +/- 40 micrograms/ml; for tetracycline, 138 +/- 65 micrograms/ml; and for sulfisoxazole, 1,466 +/- 832 micrograms/ml. The mean 8-hour percentages of the doses of drug eliminated in active form in the urine were 6.3 +/- 2.6% for chloramphenicol, 11.2 +/- 2.0% for tetracycline, and 68.5 +/- 2.1% for sulfisoxazole.

"High-pressure" liquid chromatography of sulfisoxazole and N4-acetylsulfisoxazole in body fluids.

We describe a simple, rapid chromatographic method for separating and quantitatively determining sulfisoxazole and its N4-acetyl metabolite in plasma and urine. A 100-micro L sample of plasma or urine is combined with 200 micro L of a solution containing 12 mg/L of the internal standard, N4-acetylsulfamethoxazole, in absolute methanol and centrifuged to obtain a clear supernatant solution. This solution is then eluted through a 10-micron microparticulate column with a mobile phase of 32/68 (by vol) methanol/sodium acetate buffer (0.01 mol/L, pH 4.7), at a flow rate of 1.2 mL/min. The eluted sompounds are detected by their absorption at 254 nm. We calculated concentration from the peak-height ratios of sulfisoxazole or N4-acetylsulfisoxazole to N4-acetylsulfamethoxazole. The peak-height ratio was linear with concentration in the range 0.05--200 mg/L for both drug and metabolite in plasma and urine. Because this assay can be completed within 30 min of obtaining a blood or urine sample, it should be a valuable tool in clinical drug monitoring and pharmacokinetic studies.

Simultaneous automated determination of free and total sulfisoxazole and sulfamethoxazole in plasma and urine.

A fully automated method for the determination of sulfisoxazole, N4-acetylsulfisoxazole, sulfamethoxazole, and N4-acetylsulfamethoxazole in human plasma and urine was developed. Untreated plasma is analyzed by automation of dialysis, hydrolysis, color development, and quantitation. The method has a sensitivyt limit of 2 microgram/ml of plasma and has been used successfully to determine sulfonamide levels following administration of sulfoxazole and a combination drug product containing sulfamethoxazole and trimethoprim in humans. Samples are processed at the rate of 40 per hour, with a minimum of sample handling, data reduction, and materials.

GI drug absorption in rats exposed to cobalt-60 gamma-radiation I: Extent of absorption.

The extent of absorption of sulfanilamide, bretylium tosylate, sulfisoxazole acetyl, and riboflavin was determined in rats exposed to 850 rad of cobalt-60 gamma-radiation of sham irradiated. The drug were administered orally at 1 or 5 days postirradiation, and the amount of drug excreted in the urine was used as the measure of absorption. Following intravenous drug administration, there was no difference between irradiated and control animals in the amount of drug excreted in the urine. At 1 day postirradiation, the absorption of sulfanilamide and bretylium was not affected by radiation; the absorption of sulfisoxazole acetyl and riboflavin was increased. The fraction of sulfanilamide excreted in the urine as N4-conjugate was increased at 1 day postirradiation. At 5 days postirradiation, there was no detectable difference between irradiated and control animals in the extent of drug absorption. The effects of radiation on the extent of absorption of orally administered drugs were most pronounced immediately following irradiation. Irradiation apparently does not affect the absorption of drugs that are normally well absorbed or poorly absorbed due to slow transport across the GI mucosa. Following irradiation, there may be an increase in the extent of absorption of drugs that are poorly absorbed due to low aqueous solubility or that are absorbed by a saturable transport mechanism.

Saturable first-pass metabolism of sulfisoxazole N1-acetyl in rats.

Saturable metabolism of sulfisoxazole N1-acetyl in the rat during the initial pass of the drug from the intestinal lumen through the liver following oral administration of the drug (saturable first-pass metabolism) was investigated. The fraction of the total amount of drug recovered from the urine as the N4-conjugate fraction was apparent following the intravenous administration of sulfisoxazole acetyl or the oral administration of sulfisoxazole at the same dose levels.

Effect of gastric surgery on the gastrointestinal drug absorption in man.

The effect of gastric surgery on the absorption of quinidine, ethambutol, and sulphafurazole was studied in 14 male patients, all serving as their own controls. Antrectomy with gastroduodenostomy (ABI) and selective vagotomy lowered the serum levels of all drugs significantly during the 6-hour test period. Excretion of drugs in 6-hour urine also decreased. Three patients showed practically no absorption up to 2 hours, and even therafter the absorption was lowered. Over one year after operation the urinary excretion of ethambutol, but not of the other drugs, was improved. ABI alone did not modify absorption. Preoperative gastric retention seemed to delay absorption.

Disc-agar diffusion microbiological assay procedure for determining serum and urine levels of sulfacytine and other sulfonamides.

A reasonably precise, reproducible, and sensitive microbiological procedure for directly assaying sulfacytine and other sulfonamides as antibacterially active drugs has been developed by appropriately modifying the standard disc-agar diffusion technique. Blood and urine levels as low as 3 mug/ml may be determined through the use of a strain of Escherichia coli and a chemically defined agar medium devoid of sulfonamide antagonists. Results indicate that this assay method should be a useful adjunct to the Bratton-Marshall colorimetric procedure, by permitting the direct measurement of antibacterially active drug in clinical specimens.