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The acetylcholinesterase inhibitor, acotiamide, improves gastric motility and is clinically used to treat functional dyspepsia. The present study aimed to identify the transporters involved in the distribution of acotiamide in stomach tissue. Acotiamide uptake by the gastric cancer-derived model cell line, Hs746 T, was Na + - and pH-independent. The initial uptake velocity of acotiamide was saturable with increasing concentrations of acotiamide and was inhibited by selective serotonin reuptake inhibitors, which are potent inhibitors of the plasma membrane monoamine transporter (PMAT). The uptake of acotiamide by PMAT gene-transfected HEK293 cells was saturable, with similar K m (197.9 μM) values to those of uptake by Hs 746T cells (106 μM). Moreover, immunoreactivity of PMAT was found in the gastric smooth muscle and vascular endothelial cells. These results suggest that PMAT contributes to the distribution of acotiamide in the stomach, where it exerts its pharmacological effects.

Purpose: 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.

Aims: 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., Main Methods: Distribution of [(14)C]acotiamide was evaluated using macro- and micro-autoradiography in rats and dogs., Key Findings: 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., Significance: 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., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Wiley-Liss, Inc.)

In clinical trials, acotiamide hydrochloride (acotiamide: Z-338) has been reported to be useful in the treatment of functional dyspepsia. Here, we investigated the effects of acotiamide on gastric contraction and emptying activities in rats in comparison with itopride hydrochloride (itopride) and mosapride citrate (mosapride). We also examined in vitro the compound's inhibitory effect on acetylcholinesterase (AChE) activity derived from rat stomach. In in vivo studies, acotiamide (30 and 100mg/kg s.c.) and itopride (100mg/kg s.c.) markedly enhanced normal gastric antral motility in rats. In gastric motility dysfunction models, acotiamide (100mg/kg s.c.) and itopride (100mg/kg s.c.) improved both gastric antral hypomotility and the delayed gastric emptying induced by clonidine, an α(2)-adrenoceptor agonist. In contrast, mosapride (10mg/kg s.c.) had no effect on these models. Like the AChE inhibitors itopride (30 mg/kg s.c.) and neostigmine (10 μg/kg s.c.), acotiamide (10mg/kg s.c.) also clearly enhanced gastric body contractions induced by electrical stimulation of the vagus, which were abolished by atropine and hexamethonium, whereas mosapride (3 and 10mg/kg s.c.) did not. In in vitro studies, acotiamide concentration-dependently inhibited rat stomach-derived AChE activity (IC(50)=2.3 μmol/l). In addition, stomach tissue concentrations of acotiamide after administration at 10mg/kg s.c. were sufficient to produce inhibition of AChE activity in rat stomach. These results suggest that acotiamide stimulates gastric motility and improves gastric motility dysfunction in rats by inhibiting AChE activity, and may suggest a role for acotiamide in improving gastric motility dysfunction in patients with functional dyspepsia., (Copyright © 2011 Elsevier B.V. All rights reserved.)