title: Mechanism for distribution of acotiamide, a novel gastroprokinetic agent for the treatment of functional dyspepsia, in rat stomach.
abstract: The novel gastroprokinetic agent acotiamide improves gastric motility by inhibiting acetylcholinesterase activity in stomach; however, the mechanism of distribution of acotiamide from blood to stomach has not been clarified. Here, the tissue distribution of acotiamide was investigated in rats. The tissue-to-plasma concentration ratio (K(p,app,in vivo)) for stomach decreased from 4.1 to 2.4 mL/g of tissue at steady state with increasing plasma concentrations, whereas the K(p,app,in vivo) for skeletal muscle was much lower and constant, regardless of the concentration of acotiamide in plasma. In vitro binding to stomach tissue protein exhibited a linear profile, with a predicted K(p,app,in vitro) of 2.2 from free fractions under linear conditions. Therefore, protein binding to stomach tissue might only play a limited role in the stomach distribution of acotiamide. The influx permeability (f (u,b) × PS(inf,app)) in the stomach exhibited dose-dependent saturation at the lowest range of examined blood unbound concentrations of acotiamide, whereas that in skeletal muscle exhibited only minimal dose dependence. In addition, the unbound concentration ratio of stomach to plasma (2.8) at steady state was markedly higher than unity. Taken together, these results suggest that carrier-mediated concentrative uptake processes play an important role in the distribution of acotiamide to the stomach but not skeletal muscle.
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Corporation, Ltd., Saitama 360-0111, Japan. kazuyoshi-yoshii@zeria.co.jp
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yoshii
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirayama
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Ryoko
authors.initials: R
authors.lastname: Toda
authors.forename: Junko
authors.initials: J
authors.lastname: Hasegawa
authors.forename: Mineo
authors.initials: M
authors.lastname: Takei
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Mera
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawabata
mesh_terms: D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002853:Chromatography, Liquid; D004415:Dyspepsia / Q000188:drug therapy*; D005753:Gastric Mucosa / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D013844:Thiazoles / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; D005765:Gastrointestinal Agents; D013844:Thiazoles; C410959:Z 338