Influence of indomethacin amphoteric gel on gastric ulcerogenicity and absorption of indomethacin in rats.

Indomethacin is a potent and efficacious antiinflammatory agent. However, a limiting side effect is its ability to cause gastric ulceration. This study was designed to investigate the effects of an amphoteric gel on the gastric ulcerogenicity and pharmacokinetics of indomethacin. Oral administration (5 mg/kg) in a suspension and a gel formulation were compared to an intravenous (iv) formulation of indomethacin in rats. The iv formulation administered to rats produced large severe ulcers in some rats but not in others. In contrast, the oral suspension produced small ulcers in all rats. The difference in toxicities is attributed to a centrally mediated action as a result of high plasma levels of indomethacin following iv administration, compared to locally mediated action with the suspension, resulting from local high concentrations of indomethacin on the apical epithelial surface because of the presence of indomethacin crystals. Oral administration of the gel formulation did not result in any gastric ulceration and improved the bioavailability of indomethacin to 115.5%, compared with 68.2% for the suspension. The reduced gastrointestinal toxicity of indomethacin in the gel was attributed to the gel's ability to dissolve indomethacin, preventing the localized high concentration observed with the suspension and possibly providing a gastric protectant phospholipid. The gel formulation doubled the oral bioavailability and the tmax of indomethacin compared to the suspension but did not affect the half-life. The results indicate that the local irritant effect of indomethacin, in rats, can be reduced by appropriate formulation design and suggest that the ulcerogenicity index for indomethacin can be improved by the use of an amphoteric gel formulation.