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

Pharmaceutical Research, Sep 2015

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.

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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

Physiologically-Based Pharmacokinetic and Pharmacodynamic M o d e l i n g f o r t h e I n h i b i t i o n o f A c e t y l c h o l i n e s t e r a s e b y A c o t i a m i d e , A N o v e l G a s t r o p r o k i n e t i c A g e n t for the Treatment of Functional Dyspepsia, in Rat Stomach Kazuyoshi Yoshii 0 Minami Iikura 0 Masamichi Hirayama 0 Ryoko Toda 0 Yoshihiro Kawabata 0 0 Central Research Laboratories, Zeria Pharmaceutical Co., Ltd , 2512-1 Numagami, Oshikiri, Kumagaya, Saitama 360-0111 , Japan 1 Kazuyoshi Yoshii 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. acetylcholine; acetylcholinesterase; functional dyspepsia; pharmacodynamics; pharmacokinetics - 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]. Although the pathophysiology of FD is not fully established, gastric dysmotility has been reported as a putative cause of FD. Gastric motility is mainly regulated by the cholinergic system, which is regulated by factors such as acetylcholine (ACh). ACh is released from presynaptic neurons into the synaptic cleft, where it then 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 [5–7]. 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]. 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]. These experiments suggested that acotiamide in the stomach tissue might be effective for enhancement of gastric motility as the stomach tissue concentration of acotiamide was higher than the IC50 for AChE after the subcutaneous administration of acotiamide to rats [9]. Since the stomach tissue concentration of acotiamide could be important for the pharmacological action of acotiamide, the distribution of acotiamide to the stomach was evaluated in rats [10]. In that study, acotiamide was highly distributed into the stomach after the intravenous administration of acotiamide to rats [10]. Moreover, the integration plot analysis indicated that acotiamide was uptaken by at least two stomach compartments, which rapidly and slowly equilibrated with the blood [10]. However, 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. The purpose of this study was to elucidate the relationship of the blood and stomach concentration of acotiamide with the pharmacological action. For the purpose, we developed a physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model to describe the profiles for concentration of acotiamide and ACh in rats. In this model, the stomach compartments rapidly and slowly equilibrated with the blood were assumed as vascular space and extravascular compartment in rat stomach, respectively. In addition, ACh was chosen as the marker for the (...truncated)


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Kazuyoshi Yoshii, Minami Iikura, Masamichi Hirayama, Ryoko Toda, Yoshihiro Kawabata. 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, Pharmaceutical Research, 2016, pp. 292-300, Volume 33, Issue 2, DOI: 10.1007/s11095-015-1787-y