Comparison of the Disposition of Hepatically-Generated Morphine-3-glucuronide and Morphine-6-glucuronide in Isolated Perfused Liver from the Guinea Pig

Purpose. Humans and guinea pigs metabolise morphine extensively, forming the isomers morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in relatively similar ratios. Both metabolites are formed in the liver, and their greater polarity relative to the parent aglycone may limit their permeability across hepatic membranes. This study compared the disposition of hepatically-generated M3G and M6G in perfused livers isolated from guinea pigs. Methods. Livers were perfused at 30 ml/min in a non-recirculating manner with Krebs bicarbonate buffer containing morphine (6 to 7 M). Perfusing medium, venous perfusate and bile were collected at regular intervals and concentrations of morphine, M3G and M6G determined by reversed-phase HPLC. Results. Concentrations of morphine, M3G and M6G in perfusate and the rates of biliary excretion of M3G and M6G were consistent between 20 and 50 min of perfusion. The mean (±s.d.) ratio for the rate of formation of M3G relative to M6G was 3.7 ± 1.5. A mean 33 ± 3% of morphine extracted by the liver was recovered as summed M3G and M6G. Of the M3G and M6G formed during a single passage, 19 ± 11% and 9 ± 9%, respectively, was excreted into bile; the values were significantly different (P = 0.002). Conclusions. A greater fraction of hepatically-generated M3G excreted into bile compared to that for M6G reflects differences in their relative transport across sinusoidal and canalicular membranes of hepatocytes, possibly via carrier-mediated systems.