Enterochromaffin-like cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine.
Long-term administration of some long-acting inhibitors of gastric acid secretion has been associated with the development of gastric enterochromaffin-like (ECL)-cell carcinoids in the rat. It has been argued that short-acting, surmountable histamine H2-receptor blockers such as ranitidine do not cause carcinoids. In this study, female rats (n = 100) were treated for 2 years with the histamine H2-receptor blocker ranitidine, 2 g/kg/day in the diet. Specimens from the stomachs of all rats, including 50 controls, were stained for argyrophil cells. Plasma gastrin and ranitidine levels were measured in separate groups of rats at different times during the study. The mean plasma level of ranitidine was 37.5 mumol/l, measured at midnight when the maximal level after food intake was expected. The resulting acid inhibition was associated with an approximately 3-fold increase in plasma gastrin which persisted throughout the whole period of the study. The ranitidine treatment resulted in a pronounced hyperplasia of gastric ECL cells. In 19 rats carcinoids were found, 4 of which were micro-invasive. No carcinoids were found in the control animals. The results provide further support for the gastrin mechanism, i.e. that the development of ECL-cell carcinoids in the rat gastric mucosa is a consequence of prolonged hypergastrinaemia and is not a unique effect of any individual acid-inhibiting drug.
Havu
N
N
Safety Assessment AB Astra, Södertälje, Sweden.
Mattsson
H
H
Ekman
L
L
Carlsson
E
E
D000818:Animals; D002276:Carcinoid Tumor / Q000139:chemically induced*; D004759:Enterochromaffin Cells / Q000187:drug effects; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects*; D005755:Gastrins / Q000097:blood; D011899:Ranitidine / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013274:Stomach Neoplasms / Q000139:chemically induced*; D013997:Time Factors
D005755:Gastrins; D011899:Ranitidine