The administration of hydrocortisone (HC; 75 mg/kg i.v. daily for 10 days) to rabbits significantly increased the metabolic clearance (Clm) of sulfamethazine (SMZ) from 1.92 +/- 0.05 to 2.85 +/- 0.06 liters/hr/kg (P less than 0.01). However, p.o. availability of SMZ was similar before (0.42 +/- 0.06) and after (0.39 +/- 0.03) steroid treatment. Furthermore, total liver blood flow as measured by the radioactive microsphere technique was increased (P less than 0.01) from 3.64 +/- 0.15 to 5.12 +/- 0.54 liters/hr/kg by HC treatment. Estimates of presystemic intestinal extraction and hepatic extraction were derived. These data predicted that intestinal extraction ranged from 0.11 to 0.15 in untreated rabbits and from 0.11 to 0.16 in HC-treated rabbits. Moreover, intestinal clearance was shown to contribute less than 4% to Clm of SMZ on both study days. By comparison, estimates of hepatic extraction ranged from 0.51 to 0.53, and from 0.54 to 0.56 in untreated and HC-treated rabbits, respectively. Based on the concept of a well-stirred, perfusion-limited model of hepatic elimination, the HC-induced increases in hepatic enzyme activity and blood flow were shown to make comparable contributions to the increase in hepatic clearance. It is concluded that the liver is the major site of SMZ acetylation in untreated and HC-treated, rapid acetylator rabbits. Furthermore, the increase in Clm of SMZ observed in vivo after HC treatment is attributable primarily to increases in hepatic N-acetyltransferase activity and liver blood flow.