Gastric Morphological Changes Including Carcinoid Tumors in Animals Treated with a Potent Hypolipidemic Agent, Ciprofibrate

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Abstract
Oral administration of ciprofibrate, a potent hypolipidemic compound, to rats for 2 or more weeks at doses of 20 mg/kg/day or more resulted in hypertrophy and increased eosinophilia of the oxyntic cells in the gastric mucosa. Ultrastructural evaluation revealed small secretory canaliculi with small microvilli in these cells, changes consistent with the inhibition of acid secretion. After longer administration (e.g., >2 months at 20 mg/kg/day), hyperplasia of the neuroendocrine cells (in particular, the enterochromaffin-like cells) was present in the fundic mucosa of the stomach. After life-time (2-year) administration at 10 mg/kg/day, neuroendocrine cell hyperplasia was accompanied by formation of malignant carcinoid tumors in the fundus of 5 of 59 male and 1 of 60 female rats. In contrast, administration of ciprofibrate to mice at 20 mg/kg/day for 2 months was not associated with oxyntic or neuroendocrine cell changes, a finding consistent with the lack of gastric carcinoid tumors in a 2-year mouse study. Similarly, no significant changes were induced in the marmoset stomach by doses as high as 100 mg/kg/day for 6 months. These findings are consistent with the hypothesis that the formation of gastric carcinoid tumors following ciprofibrate administration is a phenomenon that occurs specifically in those species such as the rat where this compound has significant gastric antisecretory activity.