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 car riers by cells of the mononuclear phagocyte system, mainly the Kuppfer cells, may concentrate an encapsulated drug close to the liver parenc hymal cells and facilitate its biliary excretion and enterohepatic cir culation. To test this hypothesis indomethacin was administered (10 mg /kg) in four groups of 10 rabbits each by intravenous infusion at a co nstant rate over 2 hr, either in its free form (aqueous solution) or a s nanocapsules prepared from preformed poly(DL-lactide). Unchanged dru g was assayed in plasma of the two control (sham-operated) groups and in both plasma and bile of the two bile-cannulated groups. Pharmacokin etic 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 biliar y clearance, as a result of parallel increases in bile concentration a nd biliary excretion of the drug. It was also demonstrated that nanoca psules enhance the enterohepatic circulation of indomethacin.