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The gastrin‐receptor antagonist L‐365,260 inhibits stimulated acid secretion in humans
Author(s) -
Murphy M Gail,
Sytnik Bozena,
Kovacs Thomas O G,
Mertz Howard,
Ewanik Daria,
Shingo Sumiko,
Lin Juinn H,
Gertz Barry J,
Walsh John H
Publication year - 1993
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1993.185
Subject(s) - pentagastrin , gastrin , gastric acid , cholecystokinin , medicine , endocrinology , chemistry , antagonist , receptor antagonist , secretion , basal (medicine) , placebo , receptor , pharmacology , alternative medicine , pathology , insulin
We investigated the effect of a novel gastrin—cholecystokinin‐B receptor antagonist, L‐365,260 [(3R)‐3( N ′‐3‐methylphenyl)ureido)‐1,3‐dihydro‐5‐phenyl‐2H‐1,4‐benzodiazepin‐2‐one], on gastric acid secretion in humans. In a double‐blind, four‐period crossover study, eight subjects received single oral doses of placebo or of 2.5, 10, or 50 mg L‐365,260, followed by an intravenous infusion of pentagastrin at doses of 0.05, 0.4, and 2 µg/kg/hr for successive 30‐minute periods. L‐365,260 caused a dose‐dependent inhibition of pentagastrin‐stimulated gastric acid secretion. A single oral dose of 50 mg L‐365,260 produced 50% inhibition of the gastric acid output response to pentagastrin (0.4 µg/kg/hr) when the mean (±SD) plasma L‐365,260 concentration was 502 ± 108 ng/ml. Plasma L‐365,260 concentrations (all doses combined) and the inhibition of gastric acid output 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 gastric acid output or alter plasma gastrin concentrations. L‐365,260 was 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 receptors in humans. Clinical Pharmacology and Therapeutics (1993) 54, 533–539; doi: 10.1038/clpt.1993.185