Abstract
Metabolic studies were conducted on 14C-labeled indometacin farnesil (14C-IMF) and 14C-indomethacin (14C-IND) in rats. The uptake of IMF into target cells and release of IND from IMF were also examined in vitro using 3H-IMF and 3H-IND in cultured rat snovial cells.
1. 14C-IMF, administered orally, was absorbed mainly from intestinal tract via thoracic lymph duct (12% of the dose) as unchanged from. The extent of gastrointestinal absorption was estimated to be about 20% of administered dose based on the lymphatic and portal vein absorption.
2. The level of radioactivity in the blood reached the maximum of 2.80 nmol/ml at 6 hr, followed by gradual decrease after administration of 14C-IMF dissolved in sesame oil. The extent of absorption of IMF decreased at doses greater than 5 mg/kg.
3. Maximum concentrations in the most tissues were reached at 4-6 hr after 14C-IMF dosing. The liver had the highest radioactivity level exceeding about 3 times that in the plasma, followed by adrenal and spleen with 1.5 times higher levels than in plasma at 4 hr after dosing. From these results, it was demonstrated clearly that IMF was distributed into the tissues as on unchanged form at higher levels than that in plasma, although IND was in plasma.
4. In vitro plasma protein binding of IMF to dog and human plasma was more than 98 %.
5. The uptake of IMF by cultured synovial cells was more than 70-fold greater than that of IND, and IMF was hydrolyzed to IND in the cells. The hydrolytic enzyme activity towared IMF in the cells was induced by the addition of PMN factor to the cultured medium.
6. IMF was found to be metabolized mainly by the hydrolysis of ester bond and with further release the active metabolite, IND.
7. About 14% and 91% of radioactivity were excreted in urine and feces. respectively.
