EVIDENCE FOR REVERSIBLE SEQUESTRATION OF MORPHINE IN RAT-LIVER

The residence of morphine in the systemic circulation is prolonged des pite a high systemic clearance, suggestive of significant extravascula r sequestration. The present study was conducted to test the hypothesi s that morphine binds significantly in tissues, and that the liver pla ys an important role in morphine binding. [C-14]Morphine was administe red to male Sprague-Dawley rats 55 min before unlabeled morphine or sa line. Blood C-14 increased immediately after injection of unlabeled mo rphine; the area under the blood concentration-time curve (AUG) for C- 14 increased similar to 2-fold after morphine compared with saline inj ection. Residual radioactivity in the liver was lower in morphine-trea ted rats than in controls, suggesting that unlabeled drug displaced [C -14]morphine (or a metabolite) from binding sites. To examine this phe nomenon more directly, a recirculating isolated perfused liver system was employed. [C-14]Morphine was added to the perfusate reservoir 15 m in before unlabeled morphine or saline; perfusate and bile samples wer e collected for 120 min. Upon termination of perfusion, the liver was fractionated to identify the hepatic subcellular fraction(s) in which morphine was sequestered. The perfusate AUC for [C-14]morphine was inc reased similar to 2-fold in response to unlabeled drug, consistent wit h the in vivo experiment. Morphine was associated preferentially with the cytosolic fraction, and [C-14]morphine in all relevant fractions w as reduced after administration of unlabeled morphine. In contrast, un labeled drug had no influence on derived [C-14]morphine-3-beta,D-glucu ronide. These data are consistent with significant, reversible binding of morphine in hepatic tissue.