Effects of chronic treatment with indomethacin at clinically relevant doses on intestinal tissue 6-keto prostaglandin F1 alpha and leukotriene B4 level in relation to gastroenteropathy

Abstract

This study investigated the effects of indomethacin at clinically relevant doses and its chronic usage on intestinal pathology, survival time and intestinal tissue 6-keto prostaglandin F1 alpha and leukotriene B4 level in rats during various periods with different doses. Indomethacin was administered ranging from 0.625 to 5 mg/kg. When used in doses of 0.625 and 1.25 mg/kg, indomethacin caused no apparent intestinal lesions or death during a treatment period of 30 days. On the other hand, all rats died in 7 days when 5 mg/kg of indomethacin was given. Mortality rate reached 53.3% in seven days in the group where 3.75 mg/kg indomethacin was given. The minimal dose of indomethacin, which induced intestinal ulcer and death, was 2.5 mg/kg. The main pathological findings were intestinal ulcers, but no macroscopic and microscopic changes were observed in the stomach. Intestinal tissue 6-keto prostaglandin F1 alpha and leukotriene B4 levels were quantified by enzyme immunoassay after homogenisation and extraction of tissue. In dose-dependent studies, only the dose of indomethacin, 3.75 mg/kg, significantly inhibited intestinal tissue 6-keto prostaglandin F1 alpha levels during seven days application period (197.39 +/- 24.26 vs 383.66 +/- 46.68 ng/g tissue, treatment vs control). 2.5 mg/kg of indomethacin caused no intestinal ulceration on 4th day, however, it significantly inhibited intestinal tissue 6-keto prostaglandin F1 alpha levels on 4th day in time-dependent studies (190.3 +/- 26.62 vs 383.66 +/- 46.68 ng/g tissue, treatment vs control). Neither dose-dependent nor time-dependent indomethacin administration changed intestinal tissue leukotriene B4 level. The results of this study indicated that indomethacin produced enteropathy rather than gastropathy when used chronically in clinically relevant doses in rats. Inhibition of prostaglandin synthesis, which was estimated by quantification of intestinal tissue 6-keto prostaglandin F1 alpha level, seemed not to be a prerequisite for its enteropathic effect.