DISPOSITION OF MORPHINE AND ITS 3-GLUCURONIDE AND 6-GLUCURONIDE METABOLITES DURING MORPHINE INFUSION IN THE SHEEP

A sheep preparation was used to examine the regional formation and ext raction of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6 G), relative to the regional extraction of morphine, at four morphine dose rates. On separate occasions, four ewes received a 15-min loading infusion of morphine sulfate, followed by a constant infusion at 2.5, 5, 10, or 20 mg/hr for an additional 5.75 hr. During the Sth to 6th h r of infusion, blood samples were collected simultaneously from the ao rta, pulmonary artery, hepatic vein, hepatic portal and renal veins, p osterior vena cava, and coronary and sagittal sinuses. Urine was colle cted for 48 hr. Morphine, M3G, and M6G in plasma and urine were determ ined simultaneously by HPLC. The blood/plasma concentration ratio (lam bda) for morphine, M3G, and M6G was determined in spiked ''blank'' blo od. Steady-state plasma concentrations were achieved during the sampli ng period, and dose-normalized. concentrations were independent of the infusion rate. There was significant (p < 0.05) extraction (mean +/- SD) of morphine by the liver (0.676 +/- 0.014) and kidney(0.602 +/- 0. 039), not extraction of M3G (0.106 +/- 0.046) and M6G (0.104 +/- 0.030 ) by the kidney, and net formation of M3G (-0.057 +/- 0.017) by the gu t. The mean lambda for morphine, M3G, and M6G was 1.25 +/- 0.17, 0.80 +/- 0.03, and 0.82 +/-0.09, respectively. The mean total body clearanc e of morphine with respect to blood was 1.58 +/- 0.27 liters/min. Mean (+/-SD) percentage urinary recoveries as morphine, M3G, and M6G were 14.7 +/- 8.5, 75.4 +/- 11.1, and 0.49 +/- 0.39, respectively. Data ind icate that the liver and kidney are the major organs for the eliminati on of morphine and that the kidney is the chief site for the eliminati on of the glucuronide metabolites. Furthermore, the lack of mass balan ce between the sum of morphine, M3G, and M6G in blood entering and lea ving the liver, together with the net formation of M3G by the gut, sug gests enterohepatic cycling of morphine.