Abstract
An analgesic efficacy of IMF and the metabolism were examined after oral administration of 14C-labelled indometacin farnesil (IMF) in the dog arthritis model, and were compared with those of indomethacin (IND).
1. IMF have shown the analgesic effect in a dose-dependent manner and an effective dose of IMF was greater than 3mg/kg, whereas IND was at 0.3mg/kg. Based on pharmacological study, the metabolic studies were carried out with both 14C-labelled IMF (14C-IMF) and IND (14C-IND) at a dose of 10mg/kg and 3mg/kg, respectively.
2. Cmax and AUC (0-6hr) values in the blood were not different between 14C-IMF and 14C-IND dosing, however the Tmax was greater in the case of 14C-IMF than that after 14C-IND dosing.
3. Following 14C-IMF dosing, concentrations of radioactivity in the inflamed site (synovial tissue and synovial fluid) were approx. 2 times greater than those in normal site. Radioactivity in inflamed site was present mainly as unchanged IMF, however, IND released from IMF was also present of several times lower levels than those of unchanged IMF. The levels of IMF and IND, as well as total radioactivity in inflamed site were higher at 6hr than those at 3hr. In the dosing of 14C-IND, both concentrations of radioactivity and IND in inflamed site were comparable with those in the normal sites, which levels were equal or lower when compared with those of 14C-IMF dosing.
4. Hydrolytic enzyme activity toward IMF was highest in the liver, followed by kidney. The enzyme activity was not observed in plasma, but was present in synovial fluid obtained from inflamed site.
5. Based on these results, it was demonstrated that IMF has an analgesic efficacy in dogs with carrageenin-induced arthritis. And it was suggested that IMF has a characteristic property of being transported as unchanged form into the inflamed site and then hydrolyzed to IND in the site, which might be comparable with that in human.
