Physiologically-Based Pharmacokinetic and Pharmacodynamic Modeling for the Inhibition of Acetylcholinesterase by Acotiamide, A Novel Gastroprokinetic Agent for the Treatment of Functional Dyspepsia, in Rat Stomach.
OBJECTIVE
Acotiamide, a gastroprokinetic agent used to treat functional dyspepsia, is transported to at least two compartments in rat stomach. However, the role of these stomach compartments in pharmacokinetics and pharmacodynamics of acotiamide remains unclear. Thus, the purpose of this study was to elucidate the relationship of the blood and stomach concentration of acotiamide with its inhibitory effect on acetylcholinesterase (AChE).


METHODS
Concentration profiles of acotiamide and acetylcholine (ACh) were determined after intravenous administration to rats and analyzed by physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model containing vascular space, precursor pool and deep pool of stomach.


RESULTS
Acotiamide was eliminated from the blood and stomach in a biexponential manner. Our PBPK/PD model estimated that acotiamide concentration in the precursor pool exceeded 2 μM at approximately 2 h after administration. Acotiamide inhibited AChE activity in vitro with a 50% inhibitory concentration of 1.79 μM. ACh reached the maximum concentration at 2 h after administration.


CONCLUSIONS
Our PBPK model well described the profile of acotiamide and ACh concentration in the stomach in the assumption that acotiamide was distributed by carrier mediated process and inhibited AChE in the precursor pool of stomach. Thus, Acotiamide in the precursor pool plays an important role for producing the pharmacological action.
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd, 2512-1 Numagami, Oshikiri, Kumagaya, Saitama, 360-0111, Japan. kazuyoshi-yoshii@zeria.co.jp.
Kazuyoshi
K
Yoshii
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd, 2512-1 Numagami, Oshikiri, Kumagaya, Saitama, 360-0111, Japan.
Minami
M
Iikura
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd, 2512-1 Numagami, Oshikiri, Kumagaya, Saitama, 360-0111, Japan.
Masamichi
M
Hirayama
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd, 2512-1 Numagami, Oshikiri, Kumagaya, Saitama, 360-0111, Japan.
Ryoko
R
Toda
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd, 2512-1 Numagami, Oshikiri, Kumagaya, Saitama, 360-0111, Japan.
Yoshihiro
Y
Kawabata
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004415:Dyspepsia / Q000188:drug therapy* / Q000378:metabolism; D005746:Gastric Emptying / Q000187:drug effects; D005753:Gastric Mucosa / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
D001549:Benzamides; D002800:Cholinesterase Inhibitors; D013844:Thiazoles; C410959:Z 338; D000110:Acetylcholinesterase
acetylcholine; acetylcholinesterase; functional dyspepsia; pharmacodynamics; pharmacokinetics