Following oral administration, sulfisoxazole is rapidly and completely absorbed: the small intestine is the major site of absorption, but some of the drug is absorbed from the stomach. Sulfonamides are present in the blood as free, conjugated (acetylated and possibly other forms) and protein-bound forms. The amount present as ''free'' drug is considered to be the therapeutically active form. Approximately 85% of a dose of sulfisoxazole is bound to plasma proteins, primarily to albumin; 65% to 72% of the unbound portion is in the nonacetylated form.

Maximum plasma concentrations of intact sulfisoxazole following a single 2-gm oral dose of sulfisoxazole to healthy adult volunteers ranged from 127 to 211 µg/mL (mean, 169 µg/mL) and the time of peak plasma concentration ranged from 1 to 4 hours (mean, 2.5 hours). The elimination half-life of sulfisoxazole ranged from 4.6 to 7.8 hours after oral administration. The elimination of sulfisoxazole has been shown to be slower in elderly subjects (63 to 75 years) with diminished renal function (creatinine clearance, 37 to 68 mL/min).¹ After multiple-dose oral administration of 500 mg qid to healthy volunteers, the average steady-state plasma concentrations of intact sulfisoxazole ranged from 49. 9 to 88. 8 µg/mL (mean, 63. 4 µg/mL).²

Wide variation in blood levels may result following identical doses of a sulfonamide. Blood levels should be measured in patients receiving sulfonamides at the higher recommended doses or being treated for serious infections. Free sulfonamide blood levels of 50 to 150 µg/mL may be considered therapeutically effective for most infections, with blood levels of 120 to 150 µg/mL being optimal for serious infections. The maximum sulfonamide level should not exceed 200 µg/mL, since adverse reactions occur more frequently above this concentration.

N¹-acetyl sulfisoxazole is metabolized to sulfisoxazole by digestive enzymes in the gastrointestinal tract and is absorbed as sulfisoxazole. This enzymatic splitting is presumed to be responsible for slower absorption and lower peak blood concentrations than are attained following administration of an equal oral dose of sulfisoxazole. With continued administration of acetyl sulfisoxazole, blood concentrations approximate those of sulfisoxazole. Following a single 4-gm dose of acetyl sulfisoxazole to healthy volunteers maximum plasma concentrations of sulfisoxazole ranged from 122 to 282 µg/mL (mean, 181 µg/mL) for the pediatric suspension and occurred between 2 and 6 hours postadministration. The half-life of elimination from plasma ranged from 5.4 to 7.4.

Sulfisoxazole and its acetylated metabolites are excreted primarily by the kidneys through glomerular filtration. Concentrations of sulfisoxazole are considerably higher in the urine than in the blood. The mean urinary excretion recovery following oral administration of sulfisoxazole is 97% within 48 hours, of which 52% is intact drug, with the remaining as the N⁴-acetylated metabolite. Following administration of acetyl sulfisoxazole pediatric suspension, approximately 58% is excreted in the urine as total drug within 72 hours.

Sulfisoxazole is distributed only in extracellular body fluid. It is excreted in human milk. It readily crosses the placental barrier and enters into fetal circulation and also crosses the blood-brain barrier. In healthy subjects, cerebrospinal fluid concentrations of sulfisoxazole vary; in patients with meningitis, however, concentrations of free drug in cerebrospinal fluid as high as 94 µg/mL have been reported.

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