PHARMACOKINETICS OF INDOMETHACIN ESTER PRODRUGS - GASTROINTESTINAL AND HEPATIC TOXICITY AND THE HYDROLYTIC CAPACITY OF VARIOUS TISSUES IN RATS

In order to develop a potential prodrug of indomethacin (IM) which cau ses less irritation to the gastrointestinal mucosa, the ester prodrugs [butyl ester (IM-BE) and octyl ester (IM-OE)] of IM were synthesized and evaluated for their ulcerogenic activity and hepatic injury after oral administration in rats. Additionally, the kinetics of hydrolysis of the prodrugs,were examined to characterize the tissues or organs ca pable of hydrolyzing the ester bonds. The plasma levels of IM after th e oral administration of IM-OE and IM-BE were comparatively low compar ed with those after IM, with a small bioavailability (2.1 and 15.0%, r espectively). Ulcerogenic activity and hepatic injury, expressed by de creased hepatic microsomal enzyme activities, were hardly seen after r epeated oral administration of the prodrugs, in contrast with the seve rely irritating effects of IM alone. Hydrolysis of the prodrugs was ad equately described by first-order kinetics. IM-BE was relatively rapid ly hydrolyzed in plasma, skin and whole blood, but the hydrolysis in t he intestinal mucosa and liver was very slow. The hydrolytic rates for IM-OE were exceedingly small or negligible. These results indicate th at the main part of IM-BE and IM-OE administered orally might not be h ydrolyzed to IM in the gastrointestinal tract, and that the ester prod rugs themselves were absorbed through the mucosa; also, that the hydro lysis of ester bonds would be carried out mainly in the circulatory sy stem. Consequently, IM-BE seems to be an ideal prodrug of IM.