Gastric antisecretory effects of compound BP 2-94: a histamine H3-receptor agonist prodrug.

Compound BP 2-94 is an orally available prodrug of the histamine H3-receptor agonist (R)-alpha-methylhistamine, which was found to produce higher plasma levels than the parent drug in humans. In the present study radioimmunoassay was carried out in dogs to investigate the generation of (R)-alpha-methylhistamine in vivo after intragastric administration of the prodrug. The effects of BP 2-94 on gastric acid secretion and on histamine, gastrin, and somatostatin release were also investigated. After intragastric administration of BP 2-94 (10 mg/kg), both the prodrug and (R)-alpha-methylhistamine were detected in plasma: plasma levels of (R)-alpha-methylhistamine decayed with a T1/2 of about 1 hr and displayed concentrations as high as 50-fold the EC50 of the drug at the H3 receptor for at least 2 hr. In conscious dogs provided with gastric fistula BP 2-94, administered at 10 and 30 mg/kg intragastrically, caused a dose-dependent inhibition (maximum reduction was about 80%) of the acid secretion stimulated by 2-deoxy-D-glucose, whereas (R)-alpha-methylhistamine (20 mg/kg, intragastrically) was ineffective. BP 2-94 (30 mg/kg, intragastrically) significantly reduced the acid secretion stimulated by bombesin, while leaving unaffected that induced by histamine. The increase in plasma gastrin levels induced by 2-deoxy-D-glucose, bombesin or a test meal was not significantly modified by BP 2-94 (30 mg/kg, intragastrically). In anesthetized dogs BP 2-94 (30 mg/kg, intragastrically) significantly reduced histamine release detected in the portal vein under bombesin infusion, whereas it did not modify gastrin and somatostatin plasma levels. These data indicate that BP 2-94 is a good prodrug of (R)-alpha-methylhistamine in the dog, causing an efficacious reduction of acid secretion induced by both 2-deoxy-D-glucose and bombesin. Moreover, the study of paracrine and hormonal mediators of acid secretion confirms that the main mechanism underlying inhibition of acid production induced by H3-receptor activation is the impairment of histamine release from gastric histaminocytes (possibly enterochromaffin-like cells).