title: Distribution of acotiamide, an orally active acetylcholinesterase inhibitor, into the myenteric plexus of rat and dog stomachs.
abstract: OBJECTIVE
  Acotiamide is the first-in-class drug for the treatment of functional dyspepsia. Although pharmacological and therapeutic actions of acotiamide are thought to be derived from its inhibitory effects on acetylcholinesterase (AChE), whether the concentration of acotiamide at the site of action is sufficient to inhibit AChE remains unclear. Since major site of acotiamide action is thought to be the cholinergic nerve terminals in gastric myenteric plexus, we studied the distribution of [(14)C]acotiamide into gastric myenteric plexus.
  
  
  METHODS
  Distribution of [(14)C]acotiamide was evaluated using macro- and micro-autoradiography in rats and dogs.
  
  
  RESULTS
  The results of macro-autoradiography showed the concentration of radioactivity was 27.9μM in rat stomach, which was 12 times higher than IC50 of acotiamide for rat AChE. Being different from rats, the distribution of radioactivity in the muscular layer was distinguishable from that in the mucosal layer in dog stomach. The concentration of radioactivity in the muscular layer of dog stomach (1.41μM) was approximately two-times lower than those in the mucosal layer, however, it was approximately 1.2 times higher than IC50 of acotiamide for dog AChE. The results of micro-autoradiography also showed the radioactivity distributed homogenously in the muscular layer of rat stomach, suggesting the concentration of radioactivity around the ganglion of myenteric plexus is similar to that in the muscular layer of stomach.
  
  
  CONCLUSIONS
  These findings suggest acotiamide distributes to the myenteric plexus of stomach, a putative site of acotiamide action, with adequate concentrations to inhibit AChE, in both of rat and dog stomachs.
authors.affiliation: Toxicology & Pharmacokinetics Research, Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan. Electronic address: kazuyoshi-yoshii@zeria.co.jp.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yoshii
authors.affiliation: Toxicology & Pharmacokinetics Research, Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Toxicology & Pharmacokinetics Research, Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirayama
authors.affiliation: Toxicology & Pharmacokinetics Research, Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Toda
authors.affiliation: Toxicology & Pharmacokinetics Research, Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Kinomoto
authors.affiliation: Toxicology & Pharmacokinetics Research, Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawabata
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics*; D004285:Dogs; D004415:Dyspepsia / Q000188:drug therapy; D005753:Gastric Mucosa / Q000378:metabolism*; D008297:Male; D009197:Myenteric Plexus / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000201:enzymology / Q000648:ultrastructure; D013844:Thiazoles / Q000493:pharmacokinetics*
chemical_list: D001549:Benzamides; D002800:Cholinesterase Inhibitors; D013844:Thiazoles; C410959:Z 338; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Acotiamide; Functional dyspepsia; Stomach distribution