Sex‐differences in the Oxidative and Conjugative Metabolism of Morphine in the Rat Isolated Perfused Liver

Abstract

The rat isolated perfused liver (IPL), using Sprague-Dawley rats (200–300 g) was used to investigate sex-differences in the oxidative and conjugative metabolism of morphine to normorphine and morphine-3-glucuronide (M3G), respectively. Single-pass perfusions (n = 8 for each sex) were performed at 30 mL min−1 using erythrocyte-free and protein-free perfusion medium containing 2·7 μM morphine. The steady-state concentration of morphine, M3G, normorphine and normorphine glucuronide in venous outflow and bile were measured by HPLC. In both sexes morphine was efficiently extracted by the liver. However, the mean (± s.d.) fraction escaping extraction (availability) was significantly lower (P<0·05) in males (0·137 ± 0·046) compared with females (0·275 ± 0·023) and the intrinsic clearance of morphine, calculated using the well-stirred model, was substantially higher in livers from male rats (22·3 ± 8·7 vs 10·2 ± 1·8 mL min−1 (g liver weight)−1). In male rat IPLs, 17% of eliminated morphine was recovered as normorphine and normorphine glucuronide, whereas in female rat IPLs there was no evidence for the formation of these metabolites. The partial intrinsic clearance for the metabolism of morphine to M3G was significantly higher (P<0·05) in the male rats (16·9 ± 8·5 vs 8·0 ± 1·6 mL min−1 (g liver weight)−1). The results indicate sex-differences (males > females) in both the oxidative and conjugative metabolism of morphine in the rat liver.