Vol. 282, Issue 2, 779-786, 1997

Influence of Renal Failure on the Disposition of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Sheep during Intravenous Infusion with Morphine¹

Robert W. Milne , Colin F. McLean, Laurence E. Mather, Roger L. Nation, William B. Runciman, Albert J. Rutten and Andrew A. Somogyi

Centre for Pharmaceutical Research, School of Pharmacy and Medical Sciences, University of South Australia, (R.W.M., R.L.N.), Department of Anaesthesia and Intensive Care, Flinders Medical Centre, (C.F.M., A.J.R.), Department of Anaesthesia and Intensive Care, Royal Adelaide Hospital (W.B.R.), and Department of Clinical and Experimental Pharmacology, University of Adelaide, (R.W.M., A.A.S.), Adelaide; and Department of Anaesthesia and Pain Management, University of Sydney (L.E.M.), Sydney, Australia

The influence of experimentally induced renal failure on the disposition of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was examined in seven sheep infused intravenously with morphine for 6 hr. Between 5 and 6 hr, blood was collected from the aorta, pulmonary artery, hepatic, hepatic portal and renal veins and posterior vena cava. Additional samples from the aorta and urine were collected up to 144 hr. Morphine, M3G and M6G were determined in plasma and urine by high-performance liquid chromatography. Constant concentrations of morphine, but not of M3G and M6G, were achieved in plasma between 5 and 6 hr. Significant (P < .001) extraction of morphine by the liver (0.72 ± 0.05) and kidney (0.42 ± 0.15) occurred. Compared with sheep with normal kidneys (), renal failure did not alter (P = .11) the mean total clearance of morphine (1.5 ± 0.3 liters/min); clearance by the kidney was less (P < .001). However, a paired comparison using sheep common to this study and from the study when their kidneys were normal revealed a significant reduction in mean total clearance of 25%. The renal extraction of M3G and M6G and urinary recovery of the dose as summed morphine, M3G and M6G were reduced by renal failure. The kidney metabolized morphine to M3G. The data suggest that nonrenal elimination of M3G becomes more important during renal failure.