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.

Kazuyoshi Yoshii,Minami Iikura,Ryoko Toda,Masamichi Hirayama,Yoshihiro Kawabata

doi:10.1007/s11095-015-1787-y

Kazuyoshi Yoshii, Minami Iikura + Show 3 more

Open Access

https://doi.org/10.1007/s11095-015-1787-y

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Journal: Pharmaceutical research	Publication Date: Sep 9, 2015
Citations: 7	License type: CC BY 4.0

Affiliation: Zeria Pharmaceutical (Japan)

Abstract

PurposeAcotiamide, 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).MethodsConcentration 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.ResultsAcotiamide 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.ConclusionsOur 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.

Highlights

Functional dyspepsia (FD) is a disease of subjective symptoms, including postprandial fullness, early satiation, and epigastric pain, which exhibits no organic abnormalities in the stomach [1, 2]
ACh is released from presynaptic neurons into the synaptic cleft, where it binds to ACh receptors and either affects gastric motility or is inactivated by acetylcholinesterase (AChE)
On the other hand some experiments were performed after the subcutaneous administration of acotiamide to rats to investigate the enhancement of gastric motility by acotiamide in detail because the exposure after the subcutaneous administration of acotiamide is higher than that after the oral administration of acotiamide in rats [9]

Summary

Introduction

Functional dyspepsia (FD) is a disease of subjective symptoms, including postprandial fullness, early satiation, and epigastric pain, which exhibits no organic abnormalities in the stomach [1, 2]. ACh is released from presynaptic neurons into the synaptic cleft, where it binds to ACh receptors and either affects gastric motility or is inactivated by acetylcholinesterase (AChE). This relationship suggests that gastric motility might be regulated via the inhibition of AChE activity and that AChE inhibitors might effectively treat patients with FD [3, 4]. Acotiamide was the first drug to receive approval for use in treating FD [5,6,7] This compound inhibited AChE and enhanced the gastric motility like gastric accommodation reflex and gastric emptying rate after the oral administration of acotiamide to FD patients [8]. As the role of these stomach compartments were unsettled, the relationship of the blood and stomach concentration of acotiamide with the pharmacological action remains unclear

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