Influence of protein binding and metabolic interconversion on the disposition of sulfisoxazole and its N4-acetyl metabolite by the isolated perfused rat kidney.

The renal clearances of sulfisoxazole (SX) and N4-acetylsulfisoxazole (NSX) were studied in the isolated perfused rat kidney (IPK). Studies were conducted with conventional bovine serum albumin perfusates as well as with dextran perfusates to assess the influence of perfusate protein binding on the disposition of these compounds by the IPK. The results presented herein indicate that the disposition of sulfisoxazole by the IPK involves both metabolism and excretion. The metabolism of SX to NSX is reversible and is influenced by protein binding since metabolism increased with increased free fraction (Ff). The excretion of SX and NSX reflects a complex interaction of filtration, secretion, and reabsorption. A comparison of clearance values between kidneys perfused with bovine serum albumin perfusate (Ff 0.1) and dextran perfusate (Ff 1.0) suggests that tubular secretion of SX is a function of total (unbound plus bound) rather than free (unbound) drug in the perfusate.