Biliary excretion and enterohepatic recirculation of morphine-3- glucuronide in rats

Morphine elimination is characterized by a prolonged terminal elimination phase, at least in part because of enterohepatic recirculation (EHR) of morphine as its major metabolite, morphine-3-glucuronide (M3G). This experiment was conducted to characterize M3G disposition after direct administration of the metabolite to intact or bile duct-cannulatad (BC) rats, and to develop a pharmacokinetic model of EHR for M3G. Male Sprague-Dawley intact and BC rats (N = 4/group) received a 5 mg/kg iv bolus of M3G, with serum and bile sampled at timed intervals after the dose; urine was collected in toto at the end of the experiment. M3G elimination from serum was rapid in BC rats; in contrast, M3G residence was prolonged in intact animals. M3G biliary excretion rate vs. time profiles paralleled the M3G serum concentration-time profiles in BC rats, with up to 20% of the dose recovered as M3G in bile. The remainder of the dose (80%) was recovered in urine as unchanged M3G. No morphine could be detected in urine after M3G administration. To confirm that biliary elimination of M3G occurred following uptake by the liver, M3G was administered to isolated perfused rat livers (N = 4). Up to 20% of the M3G dose was recovered in bile after 90 min, suggesting that systemic M3G can gain access to the liver and contribute to EHR. Both mean residence time and steady-state volume of distribution were significantly greater in intact rats, presumably because of EHR. A pharmacokinetic model of EHR was developed to describe M3G serum concentration vs. time profiles in intact and BC rats and the biliary excretion rate vs. time profile in BC rats. Two pharmacokinetic compartments were necessary to describe M3G disposition in serum; three consecutive recycling compartments were required to describe the secondary EHR peak. The results of these studies suggest that M3G of both hepatic and extrahepatic origin can contribute to EHR of morphine.