Comparative disposition of morphine-3-glucuronide during separate intravenous infusions of morphine and morphine-3-glucuronide in sheep: Importance of the kidney

The disposition of morphine-3-glucuronide (M3G) in sheep was compared during separate constant infusions of morphine and M3G. Five ewes received a 15-min loading dose, followed by a constant infusion of morphine sulfate (10 mg/hr) or M3G (4 mg/hr for 4 sheep, 7.5 mg/hr for 1 sheep) for a further 5.75 hr. During the 5th-6th hr of infusion, blood was collected simultaneously from the aorta, pulmonary artery, hepatic vein, hepatic portal vein, renal vein, and posterior vena cava. Additional samples were collected from the aorta from 0 to 5 hr and from 6 to 48 hr. Urine was collected via an indwelling catheter from 0 to 6 hr, with further free-flowing urine up to 48 hr. An HPLC assay was used to determine simultaneously morphine, M3G, and morphine-6-glucuronide (M6G) in plasma and urine. Constant concentrations of morphine, M3G, and M6G in plasma were achieved during the 5- to 6-hr period of infusion with morphine, as were the concentrations of M3G while M3G was infused. Regional net extraction ratios and total and regional clearances were calculated during the 5- to 6-hr period. After the infusions were ceased, there was prolonged elimination of M3G formed in situ from morphine compared to when infused as M3G. No morphine or M6G was detected in the plasma during and after infusion with M3G, nor were they found in urine collected up to 6 hr. During infusion with morphine, there was significant (p < 0.05) net extraction of morphine by the liver (mean ± SD of 0.71 ± 0.03) and kidney (0.59 ± 0.07), net extraction of M3G (0.11 ± 0.04) and M6G (0.12 ± 0.04) by the kidney, and net formation of M3G by the gut (-0.047 ± 0.009). During infusion with M3G, there was significant (p < 0.05) net extraction of M3G by the kidney only (0.10 ± 0.04), which was not significantly different (p > 0.05) from its extraction during morphine infusion. The total body clearance of morphine with reference to blood was 1.86 ± 0.54 liter/min, whereas that for M3G was 0.160 ± 0.044 liter/min. With reference to plasma, the renal excretory clearance of M3G during the infusion of morphine (0.158 ± 0.040 liter/min) was significantly different (p < 0.05) from the value obtained when M3G was infused (0.098 ± 0.031 liter/min). Mean urinary recoveries of the doses of morphine and M3G were 77 ± 8% and 84 ± 13%, respectively. It is proposed that the prolonged elimination of generated M3G from plasma may be due to any Combination of its continued formation from body stores of morphine, enterohepatic cycling, and a diffusional barrier into venous blood from its site of formation within the liver. The lack of mass balance between the sum of morphine, M3G, and M6G taken up by the kidney during the infusion of morphine, or of M3G taken up during the infusion of M3G, compared with that excreted in urine suggests that the predominant metabolite, M3G, whether from arterial blood or formed in situ, is further metabolized or is still accumulating within the kidney up to 6 hr. Furthermore, the majority of the M3G formed from morphine within the tubular cells of the kidney passes into urine rather than into renal venous blood.