Demonstration of cell sidedness in hepatic transfer of morphine and morphine glucuronide in the rat

Abstract

The purpose of this study was to demonstrate hepatic cell sidedness for the transfer of [ 14Cjmorphine and [ 14C]morphine glucuronide. A tracer dose of [ 14C]morphine was administered by segmented retrograde intrabiliary injection into the bile duct cannula of the urethane-anesthetized rat or the in situ isolated perfused liver preparation. The bile from the first, and the single pass perfusate from the second preparation, respectively, were analyzed for the radioactive components. Various doses of morphine were given intraportally in these preparations 5 min before the [ 14C]rnorphine to influence the recovery of the radioactive components. As the dose of morphine increased, the recovery in bile of [ 14C]morphine glucuronide decreased while [ 14C]morphine remained unchanged. In the perfusate, the morphine loading increased the recovery of [ 14C]morphine, but the [ 14C]Cimorphine glucuronide content was unchanged. These sets of results indicated that morphine loading inhibited the formation of morphine glucuronide by isotope dilution, which should have led to an increase in [ 14C]morphine in the cell. Because of the presence of cell sidedness, the increased intracellular [ 14C]morphine was directed toward the perfusate and not toward the bile. The decrease in [ 14C]morphine glucuronide synthesis was manifested by a decrease in its excretion into bile, but not into perfusate. Further demonstration of cell sidedness was obtained by manipulation of these systems by chlordecone and trans-stilbene oxide pretreatment of the rats. The directionality of flow of [ 14C]morphine and [ 14C]morphine glucuronide out of the liver emanates from liver cell sidedness.