Morphine (2.5 mg/kg) was administered iv to intact (I), bile duct-cannulated (BC), and bile duct-cannulated--renal-ligated (BC-RL) rats (n = 4 per group) to investigate the extent of enterohepatic recirculation and renal metabolism of the drug. A decrease in the serum area under the concentration-time curve (AUC) was observed for the BC in comparison with I rats. From these AUC values, it was determined that approximately 16% of the administered dose was subject to enterohepatic recirculation. In addition, a statistically significant (p less than 0.05) decrease in the systemic clearance of morphine was observed in the BC-RL rats compared with the BC animals (55.2 +/- 17.2 versus 31.4 +/- 8.5 mL/min/kg). This decrement in systemic clearance appeared to be the result of a significant decrease in the formation clearance of morphine glucuronide after ligation of the renal pedicles (23.2 +/- 4.8 versus 10.9 +/- 5.0 mL/min/kg). Renal metabolic clearance was calculated as 15.7 mL/min/kg, accounting for 28.5% of the systemic clearance of morphine. Hepatic clearance (31.4 +/- 8.5 mL/min/kg) accounted for 56.8% of total systemic clearance.