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At least 19 recordsLinked to original sources
PubMed1979

Effect of serum protein binding on sulfisoxazole distribution, metabolism, and excretion in rats.

This investigation determined the effect of serum protein binding on the kinetics of sulfisoxazole distribution, metabolism, and excretion. Adult rats, whose serum free fraction of sulfisoxazole (at a total concentration of 81 +/- 6 micrograms/ml) was 0.05-0.24, received a rapid intravenous injection of 20 mg/kg. Sulfisoxazole concentrations in plasma declined biexponentially with time. There were pronounced and reproducible interindividual differences in the total, metabolic, and renal sulfisoxazole clearances, each positively correlated with the serum free fraction of sulfisoxazole. The renal sulfisoxazole clearance had a component unaffected by serum protein binding. The apparent central compartment volume increased with an increasing serum free sulfisoxazole fraction, but the latter had not apparent effect on the first exponential term of the biexponential equation describing sulfisoxazole elimination kinetics in rats. Serum protein binding was a major determinant of intersubject differences in sulfisoxazole excretion and biotransformation kinetics.

Animals↗
PubMed1985

Pharmacokinetics of sulfisoxazole in renal transplant patients.

We studied the elimination of sulfisoxazole in eight renal transplant patients. The patients received sulfisoxazole prophylactically for urinary tract infection commencing 7 days postoperatively. The renal elimination of sulfisoxazole (unbound renal clearance) was decreased in this patient population and was highly correlated with creatinine clearance. The unbound metabolic clearance and apparent unbound formation clearance of N4-acetyl sulfisoxazole did not differ from values found in healthy volunteers. The protein binding was marginally lower in this patient population than in healthy subjects after a single dose. The reduced binding was compatible with a reduced albumin concentration. In contrast to the situation for healthy subjects, the binding of sulfisoxazole decreased upon multiple dosing. This is probably due to a relatively higher sulfisoxazole and N4-acetyl sulfisoxazole-to-albumin ratio in this patient population than in healthy subjects. No complications of sulfisoxazole therapy were seen, although in three subjects concentration of the N4-acetyl sulfisoxazole in urine exceeded its theoretical solubility on a few occasions.

Acetylation↗
PubMed1982

Comparison of the disposition of total and unbound sulfisoxazole after single and multiple dosing.

Plasma concentrations of total and unbound sulfisoxazole were followed after single intravenous and oral doses of 1 g sulfisoxazole and during a 500-mg, four-time-a-day dosing regimen in six healthy males, using a specific high pressure liquid chromatographic assay method. Saturable plasma protein binding was observed at total concentrations above 80-100 mg/liter. The clearance of sulfisoxazole was 18.7 +/- 3.9 ml/min for total drug and 232 +/- 64 ml/min for unbound drug. Renal elimination, on the average, accounted for 49% of the clearance of sulfisoxazole. The apparent volume of distribution for total drug was 10.9 +/- 2.0 liters and 136 +/- 36 liters for unbound drug, indicating that sulfisoxazole is primarily distributed extracellularly. Accumulation of N4-acetyl-sulfisoxazole during multiple dosing did not affect the disposition of sulfisoxazole. Adjusting for variable renal clearances between oral and intravenous administration and using the unbound plasma concentrations, the bioavailability for an oral dose of sulfisoxazole was found to be 0.95 +/- 0.04.

Administration, Oral↗
PubMed2006

Sulfisoxazole, an endothelin receptor antagonist, protects retinal neurones from insults of ischemia/reperfusion or lipopolysaccharide.

Endothelins exert pathological effects in the eye and much interest centres on their role in causing retinal neuronal death in ischemic diseases like glaucoma. In the present study the influence of the non-selective endothelin antagonist, sulfisoxazole on raised intraocular pressure-induced ischemia to the rat retina was investigated. Moreover, in vitro studies on primary rat retinal cultures were undertaken to see whether sulfisoxazole is able to blunt the toxic effect of lipopolysaccharide (LPS) to retinal neurones. In order to determine whether sulfisoxazole provides protection to the retina the a- and b-wave amplitudes of the electroretinogram (ERG), the localisation of retinal choline acetyltransferase (ChAT), nitric oxide synthase (nNOS) and Thy-1 and the retinal mRNA levels of Thy-1 and FGF-2 were deduced in retinas subjected to ischemia in the absence or presence of sulfisoxazole. The results showed that the ischemia-induced changes to the a- and b-wave amplitudes of the ERG and changes associated with the localisation of ChAT, nNOS and Thy-1 to be significantly blunted by sulfisoxazole. However, while the ischemia-induced changes to Thy-1 and FGF-2 mRNAs were reduced by sulfisoxazole, the reduction was non-significant. The in vitro studies provided support for the protective effect of sulfisoxazole. Here, it was clearly shown that sulfisoxazole attenuated the elevation of nitric oxide (deduced by measuring nitrite) and the reduction in numbers of GABA-containing neurones caused by LPS. The present study provides evidence for the first time that endothelin antagonist can protect the retina from ischemic-like insults as occurs in glaucoma.

Animals↗
PubMed1985

Binding and disposition of sulfisoxazole in alcoholic cirrhosis.

The disposition of sulfisoxazole was studied in six male patients hospitalized with biopsy-proven Laennec's alcoholic cirrhosis and six normal, healthy volunteers. Four of the patients were restudied at a time their liver disease had improved clinically. On the average, compared to the normal group, the metabolism of sulfisoxazole (clearance values with respect to unbound concentration values) appears to be unaltered for the cirrhotic patients. For patients with alcoholic cirrhosis having normal renal function for age and weight, the renal elimination of sulfisoxazole was normal. For those subjects with decreased renal function, the renal clearance of sulfisoxazole appeared to be disproportionately decreased, as evidenced by a lower-than-normal sulfisoxazole renal clearance-to-creatinine clearance values. The apparent steady-state volume of distribution of unbound sulfisoxazole was not altered in cirrhotic patients when compared to normal subjects, while the apparent volume of distribution of total drug increased by more than what could be expected from protein binding changes alone. The elimination rate constant did not differ from values found in normals. These data suggest that the total binding capacity of sulfisoxazole in cirrhotic patients is not different from that of normal subjects.

Adult↗
PubMed2003

The effect of pH and triethanolamine on sulfisoxazole complexation with hydroxypropyl-beta-cyclodextrin.

A novel complexation of sulfisoxazole with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was studied. Two systems were used: binary complexes prepared with HP-beta-CD and multicomponent system (HP-beta-CD and the basic compound triethanolamine (TEA)). Inclusion complex formation in aqueous solutions and in solid state were investigated by the solubility method, thermal analysis (differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)), Fourier-transform infrared spectroscopy (FT-IR) and dissolution studies. The solid complexes of sulfisoxazole were prepared by freeze-drying the homogeneous concentrated aqueous solutions in molar ratios of sulfisoxazole:HP-beta-CD 1:1 and 1:2, and sulfisoxazole:TEA:HP-beta-CD 1:1:2. FT-IR and thermal analysis showed differences among sulfisoxazole:HP-beta-CD and sulfisoxazole:TEA:HP-beta-CD and their corresponding physical mixtures and individual components. The HP-beta-CD solubilization of sulfisoxazole could be improved by ionization of the drug molecule through pH adjustments. However, larger improvements of the HP-beta-CD solubilization are obtained when multicomponent systems are used, allowing to reduce the amount of CD necessary to prepare the target formulation.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1985

Sulfisoxazole prophylaxis of middle ear effusion and recurrent acute otitis media.

The efficacy of sulfisoxazole prophylaxis was evaluated in 32 otitis-prone children in a double-blind cross-over clinical trial. During the sulfisoxazole therapy, seven patients (22%) had nine episodes of acute otitis media (AOM) while 20 patients (63%) receiving placebo had 36 episodes of AOM (P = .001). Although sulfisoxazole appeared to be beneficial in patients aged 2 to 5 years, statistically significant efficacy was noted only in children under 2 years of age. Otitis media with effusion persisting for more than five weeks was observed in ten children (31%) during sulfisoxazole therapy and in 14 children (44%) during the placebo period (P greater than .975). Sulfisoxazole therefore appears effective in preventing recurrent symptomatic AOM but not in reducing the frequency of persistent otitis media with effusion. The importance of careful follow-up of children receiving long-term sulfisoxazole therapy for prevention of recurrent AOM is stressed.

Acute Disease↗
PubMed1990

Effects of cefotaxime on the serum protein binding of sulfisoxazole.

The possible acylating effects of cefotaxime on sulfisoxazole binding to serum proteins were evaluated in vitro in samples of human sera incubated with 50-1000 micrograms ml-1 cefotaxime at 37 degrees for 1 h and then dialyzed against saline. This incubation resulted in concentration-related increases in the free fraction of sulfisoxazole (+25 per cent, +30 per cent, and +45 per cent, with 250, 500, and 1000 micrograms ml-1 cefotaxime, respectively). Sulfisoxazole binding was also studied in samples of sera from patients given prophylactic cefotaxime (3 g d-1, IV) following elective surgery. Sulfisoxazole free fraction increased from 7.6 +/- 0.7 per cent in samples obtained before starting treatment to 9.2 +/- 0.8 per cent 24 h thereafter, and to 10.4 +/- 1.0 per cent after 5 days of treatment, but this difference was not statistically significant. A Scatchard plot of pooled samples showed a reduction in overall affinity (from 2.38 X 10(-4) M to 1.77 X 10(-4) M) without changes in the number of binding sites. The effects of cefotaxime on sulfisoxazole binding and kinetics were also studied experimentally in the rabbit. Treatment with 30 mg kg-1 cefotaxime t.i.d. for 2 days increased the unbound fraction of sulfisoxazole in vivo, from 17.2 +/- 2.9 per cent to 27.3 +/- 3.6 per cent (p less than 0.02). Treatment with high doses of cefotaxime, and perhaps other 3-acetoxymethylcephalosporins, may result in changes in the serum protein binding of some acidic drugs.

Animals↗
PubMed1984

Pharmacokinetics of sulfisoxazole in young and elderly subjects.

The pharmacokinetics of sulfisoxazole was studied in 6 elderly (age 63-75 years) and 7 young (age 22-37 years) healthy nonsmoking volunteers following the oral administration of 2 g of Gantrisin. The plasma levels of sulfisoxazole obtained in the postabsorption phase were higher in the elderly subjects. There was no significant variation between the two groups of volunteers in the absorption rate constant, Cmax, bioavailability, the fraction of the dose of sulfisoxazole excreted unchanged, the area under the plasma curve of the N4-acetyl conjugate formed, and in the apparent volume of distribution of the drug. The tmax value and plasma half-life of sulfisoxazole were significantly longer, and the total body and renal clearances of the drug decreased in the elderly subjects. Diminished renal function as estimated by the creatinine clearance and urinary flow may explain the slower elimination of sulfisoxazole in the elderly subjects. Therefore, advancing age should be considered as a factor in the adjustment of sulfisoxazole dosage.

Adult↗
PubMedDate not supplied

Surgically affected sulfisoxazole pharmacokinetics in the morbidly obese.

Intestinal bypass surgery in 4 morbidly obese female (110-150 kg) had no permanent effect on the rate or amount of sulfisoxazole absorption. The loss of weight up to 44 per cent within an individual over a year's time had no significant effect on the apparent volumes of distribution or other pharmacokinetic parameters of sulfisoxazole and its N4-acetylsulfisoxazole metabolite. Dosing of this drug on a mg kg-1 basis is contraindicated. Renal clearances of sulfisoxazole were reasonably constant within a study but those of the N4-acetylsulfisoxazole decreased with time. Integrated pharmacokinetic models were applied to plasma and urine data to estimate the metabolic clearance of sulfisoxazole and the apparent volume of distribution of the N4-acetylsulfisoxazole. Sulfisoxazole solution is absorbed readily by primarily a zero order process after a short lag period, indicative of rate-determining gastric emptying. The classical Bratton-Marshall assays were compared with an HPLC assay of both drug and metabolite. There was greater confidence in plasma levels of the metabolite from the HPLC method.

Adult↗
PubMed1979

Effect of sulfisoxazole on pharmacokinetics of free and plasma protein-bound bilirubin in experimental unconjugated hyperbilirubinemia.

The effect of sulfisoxazole on the time course of free (unbound) bilirubin concentrations in plasma was studied. Normal adult rats were made hyperbilirubinemic by continuous intravenous infusion of bilirubin. Sulfisoxazole was administered by either rapid intravenous injection or slow intravenous infusion, and the plasma concentrations of free and total (free plus bound) unconjugated bilirubin were determined as a function of time. Rapid injection of sulfisoxazole caused a rapid and pronounced decrease of total bilirubin concentrations in plasma but had only a transient effect on the concentration of free bilirubin. Slow infusion of sulfisoxazole caused a gradual and eventually pronounced decrease of total bilirubin concentrations in plasma but had no apparent effect on the concentration of free bilirubin at any time. These results are consistent with recently developed pharmacokinetic theory according to which the plasma clearance of total bilirubin should increase upon administration of a displacing agent while the plasma clearance of free bilirubin should remain unchanged. Bilirubin-induced encephalopathy caused by sulfisoxazole or other displacing agents may be due to very transient elevations of free bilirubin concentrations in plasma of infants with elevated plasma concentrations of total bilirubin and the consequent redistribution of the pigment to extravascular sites, including the brain.

Animals↗
PubMed1982

Comparison of serum bilirubin levels in humans and two monogastric animal species after a single administration of sulfisoxazole.

Administration of sulfonamides during periods of hepatobiliary failure or hepatic immaturity increases the toxic potential of unconjugated or indirect bilirubin. A small but statistically significant increase of indirect, or unconjugated bilirubin was noted in dogs after oral administration of sulfisoxazole (100 mg/kg). A similar increase was not observed in swine after oral or intravenous administration of sulfisoxazole (100 mg/kg) or in humans (approximately 28 mg/kg) after oral administration or in dogs (100 mg/kg) after intravenous administration. Total and conjugated bilirubin showed small but statistically significant increases and were significantly correlated in dogs after oral and intravenous administration of sulfisoxazole (100 mg/kg) and in swine after oral administration of sulfisoxazole (100 mg/kg). There was a significant negative correlation between conjugated and indirect bilirubin, while total bilirubin increased in dogs after oral and intravenous administration of sulfisoxazole. These data illustrate a difference in species and administration route when attempting to assess the potential toxicity of bilirubin.

Administration, Oral↗