THE GASTRIN-RECEPTOR ANTAGONIST L-365,260 INHIBITS STIMULATED ACID-SECRETION IN HUMANS

We investigated the effect of a novel gastrin-cholecystokinin-B recept or antagonist, L-365,260 -1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2- one], on gastric acid secretion in humans. In a double-blind, four-per iod crossover study, eight subjects received single oral doses of plac ebo or of 2.5, 10, or 50 mg L-365,260, followed by an intravenous infu sion of pentagastrin at doses of 0.05, 0.4, and 2 mug/kg/hr for succes sive 30-minute periods. L-365,260 caused a dose-dependent inhibition o f pentagastrin-stimulated gastric acid secretion. A single oral dose o f 50 mg L-365,260 produced 50% inhibition of the gastric acid output r esponse to pentagastrin (0.4 mug/kg/hr) when the mean (+/- SD) plasma L-365,260 concentration was 502 +/- 108 ng/ml. Plasma L-365,260 concen trations (all doses combined) and the inhibition of gastric acid outpu t were correlated with a correlation coefficient of r = 0.45 (p < 0.05 ). Single oral doses of L-365,260 up to 50 mg did not inhibit basal ga stric acid output or alter plasma gastrin concentrations. L-365,260 wa s well tolerated at oral doses up to 50 mg. These findings show that L -365,260 is an orally active antagonist at gastrin-cholecystokinin-B r eceptors in humans.