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
Kazuyoshi YoshiiYoshihiro Kawabata

Abstract

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). 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. 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. 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 p...Continue Reading

References

Feb 1, 1991·Journal of Pharmacokinetics and Biopharmaceutics·A Bernareggi, M Rowland
Oct 1, 1994·Clinical Pharmacology and Therapeutics·W J Jusko, H C Ko
Aug 1, 1993·Journal of Pharmacokinetics and Biopharmaceutics·N L DaynekaW J Jusko
Sep 29, 2001·Advanced Drug Delivery Reviews·B AgoramM B Bolger
Jun 19, 2002·Antimicrobial Agents and Chemotherapy·Mahboubeh Hosseini-Yeganeh, Andrew J McLachlan
Jul 1, 1961·Biochemical Pharmacology·G L ELLMANR M FEATHER-STONE
Dec 13, 2006·Journal of Gastroenterology·Yohei MizutaShigeru Kohno
Jun 27, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Markus FridénMargareta Hammarlund-Udenaes
May 14, 2008·Gastroenterology·Mitchell L Schubert, David A Peura
Oct 23, 2008·Current Opinion in Pharmacology·Jan Tack
Apr 23, 2010·Biological & Pharmaceutical Bulletin·Tatsuya KikuchiToshiaki Irie
Jul 9, 2010·Drug Metabolism and Pharmacokinetics·Yoshihiko ItoShizuo Yamada
Sep 22, 2011·Current Opinion in Gastroenterology·Jan TackPieter Janssen
Mar 6, 2012·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·H KusunokiJ Tack
Mar 7, 2013·Journal of Pharmaceutical Sciences·Muhammad Waqas SadiqMargareta Hammarlund-Udenaes
Jul 25, 2013·Drugs·Mary L NowlanLesley J Scott
Jun 3, 2014·Expert Opinion on Drug Metabolism & Toxicology·Yan SunRichard W McCallum
Nov 22, 2014·Fluids and Barriers of the CNS·Xiaomei ChenMargareta Hammarlund-Udenaes

❮ Previous
Next ❯

Citations

Aug 19, 2016·The Journal of Pharmacology and Experimental Therapeutics·Ikumi Ishibashi-ShiraishiTatsuro Tanaka

❮ Previous
Next ❯

Methods Mentioned

BETA
protein assay

Software Mentioned

WinNonlin

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.