Presystemic elimination of morphine in anesthetized rabbits. Contribution of the intestine, liver, and lungs

To assess the role of the intestine and the lung in the first-pass uptake of morphine relative to that of the liver, five groups of 6-7 New Zealand rabbits were used. A control group of conscious rabbits received 2 mg/kg of morphine iv. The remaining groups included anesthetized rabbits who received morphine into the aortic cross (2 mg/kg), the jugular vein (2 mg/kg), the portal vein (14 mg/kg), or into the duodenum (20 mg/kg). Multiple blood samples were withdrawn for 3 hr from the abdominal aorta, and morphine and morphine-6-glucuronide were assayed by HPLC. Anesthesia and surgery decreased morphine presystemic clearance from 264 +/- 14 to 194 +/- 12 ml/min/kg (p < 0.05). When morphine was injected into the aortic cross, the area under morphine plasma concentration-time curve (AUCM 0-->infinity) normalized by the dose was 7.81 +/- 0.56 10(-3) kg min/ml, a value that decreased to 5.26 +/- 0.36 (p < 0.05), 2.50 +/- 0.35 (p < 0.05), and 0.87 +/- 0.10 (p < 0.05) 10(-3) kg min/ml when morphine was injected before the lung, liver, or intestine, respectively. The extraction ratio of morphine by the lung, liver, and intestine was 0.33, 0.52, and 0.65, respectively. Compared with the aortic route, the AUCM6G 0-->infinity normalized by the dose ratio tended to be greater (p > 0.05) when morphine was injected into the jugular and portal veins, suggesting that morphine-6-glucuronide is not the major product result of morphine first-pass uptake.(ABSTRACT TRUNCATED AT 250 WORDS)