INFLUENCE OF POLY(DL-LACTIDE) NANOCAPSULES ON THE BILIARY CLEARANCE AND ENTEROHEPATIC CIRCULATION OF INDOMETHACIN IN THE RABBIT

Following intravenous administration, the uptake of colloidal drug carriers by cells of the mononuclear phagocyte system, mainly the Kuppfer cells, may concentrate an encapsulated drug close to the liver parenchymal cells and facilitate its biliary excretion and enterohepatic circulation. To test this hypothesis indomethacin was administered (10 mg/kg) in four groups of 10 rabbits each by intravenous infusion at a constant rate over 2 hr, either in its free form (aqueous solution) or as nanocapsules prepared from preformed poly(DL-lactide). Unchanged drug was assayed in plasma of the two control (sham-operated) groups and in both plasma and bile of the two bile-cannulated groups. Pharmacokinetic analysis led to the conclusion that the uptake of nanocapsules by liver macrophages reduces the concentration of the drug by enhancing its total clearance. This enhancement was due to an increase in biliary clearance, as a result of parallel increases in bile concentration and biliary excretion of the drug. It was also demonstrated that nanocapsules enhance the enterohepatic circulation of indomethacin.