Claudia Bachlechner, Gabriela Krist, Martin Kapferer
Sep 1, 2011
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Journal
Digestive Diseases and Sciences
Abstract
Misoprostol, a synthetic prostaglandin E1 methyl ester analog, has been shown to be effective clinically for the treatment of duodenal ulcers. Misoprostol inhibits acid secretion in several species, including man. In this study, isolated canine parietal cells were used to: (1) evaluate the effect of misoprostol on acid secretion stimulated by various substances, (2) study the metabolism of misoprostol, and (3) compare the antisecretory activity of misoprostol with its metabolites. Isolated canine parietal cells were obtained by sequential treatment of fundic mucosa with collagenase and EDTA, followed by enrichment via Ficoll gradients. The accumulation of [14C]aminopyrine by parietal cells was used as an index of acid secretion. [3H]Misoprostol was incubated with parietal cells and its metabolites were analyzed by high-performance liquid chromatography. Misoprostol (10-9-10 -7 M) inhibited histamine-stimulated acid secretion in a dose-dependent manner with an IC50 of 2-3 x 10 -9 M. Misoprostol (10 -7 M) did not significantly inhibit acid secretion stimulated by carbachol (C) or dibutyryl cAMP (DBcAMP), and it modestly inhibited forskolinstimulated acid secretion in a dose-independent manner (<40%). Cimetidine also reduced forskolinstimulated acid secretion. Misoprostol was deesterified within 5 min to its acid form, and subsequently converted by [3-oxidation to the tetranor of the acid metabolite. The acid metabolite was as potent as misoprostol in inhibiting histamine-stimulated acid secretion, but the [3-oxidation product was inactive a t l txM. These results indicate that misoprostol (1) had a much greater inhibitory effect on acid secretion stimulated by histamine than by C, DBcAMP, or forskolin; (2) was rapidly converted to its acid form, which may contribute to its antisecretory activity; and (3) was subsequently converted via its acid form to an inactive [3-oxidation metabolite.