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.