title: Gastric antisecretory effects of compound BP 2-94: a histamine H3-receptor agonist prodrug.
abstract: 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).
authors.affiliation: Department of Veterinary Clinic, Section of Pharmacology and Toxicology, University of Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Soldani
authors.forename: S
authors.initials: S
authors.lastname: Bertini
authors.forename: A
authors.initials: A
authors.lastname: Rouleau
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
authors.forename: G
authors.initials: G
authors.lastname: Coruzzi
mesh_terms: D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism*; D005755:Gastrins / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D007097:Imines / Q000008:administration & dosage / Q000494:pharmacology*; D008761:Methylhistamines / Q000494:pharmacology; D010636:Phenols / Q000008:administration & dosage / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013004:Somatostatin / Q000378:metabolism
chemical_list: D005755:Gastrins; D017442:Histamine Agonists; D007097:Imines; D008761:Methylhistamines; D010636:Phenols; D011355:Prodrugs; D018100:Receptors, Histamine H3; C106714:BP 2-94; D013004:Somatostatin; C069357:alpha-methylhistamine; D006632:Histamine; D003847:Deoxyglucose; D001839:Bombesin