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Article

The Impact of Dextran Sodium Sulfate-Induced Gastrointestinal Injury on the Pharmacokinetic Parameters of Donepezil and Its Active Metabolite 6-O-desmethyldonepezil, and Gastric Myoelectric Activity in Experimental Pigs

by
Jan Bures
1,*,
Ilja Tacheci
1,
Jaroslav Kvetina
1,
Vera Radochova
2,
Lukas Prchal
3,
Darina Kohoutova
1,4,
Martin Valis
5,
Martin Novak
3,6,
Rafael Dolezal
3,
Marcela Kopacova
1,
Stanislav Rejchrt
1,
Vit Sestak
7,
Veronika Knoblochova
1,
Eva Peterova
1 and
Jana Zdarova Karasova
3,8
1
2nd Department of Internal Medicine-Gastroenterology, Charles University Faculty of Medicine in Hradec Kralove and University Hospital, 500 03 Hradec Kralove, Czech Republic
2
Animal Laboratory, Faculty of Military Health Sciences, University of Defence, 500 01 Hradec Kralove, Czech Republic
3
Centre of Biomedical Research, University Hospital, 500 05 Hradec Kralove, Czech Republic
4
The Royal Marsden Hospital NHS Foundation Trust, London SW3 6JJ, UK
5
Department of Neurology, Charles University Faculty of Medicine in Hradec Kralove and University Hospital, 500 03 Hradec Kralove, Czech Republic
6
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Charles University Faculty of Pharmacy, 500 05 Hradec Kralove, Czech Republic
7
Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czech Republic
8
Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, 500 01 Hradec Kralove, Czech Republic
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(8), 2160; https://doi.org/10.3390/molecules26082160
Submission received: 20 March 2021 / Revised: 5 April 2021 / Accepted: 7 April 2021 / Published: 9 April 2021
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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Abstract

Gastrointestinal side effects of donepezil, including dyspepsia, nausea, vomiting or diarrhea, occur in 20–30% of patients. The pathogenesis of these dysmotility associated disorders has not been fully clarified yet. Pharmacokinetic parameters of donepezil and its active metabolite 6-O-desmethyldonepezil were investigated in experimental pigs with and without small intestinal injury induced by dextran sodium sulfate (DSS). Morphological features of this injury were evaluated by a video capsule endoscopy. The effect of a single and repeated doses of donepezil on gastric myoelectric activity was assessed. Both DSS-induced small intestinal injury and prolonged small intestinal transit time caused higher plasma concentrations of donepezil in experimental pigs. This has an important implication for clinical practice in humans, with a need to reduce doses of the drug if an underlying gastrointestinal disease is present. Donepezil had an undesirable impact on porcine myoelectric activity. This effect was further aggravated by DSS-induced small intestinal injury. These findings can explain donepezil-associated dyspepsia in humans.
Keywords: 6-O-desmethyldonepezil; dextran sodium sulfate; donepezil; electrogastrography; experimental pigs; gastric myoelectric activity; organ distribution; pharmacokinetics; video capsule enteroscopy 6-O-desmethyldonepezil; dextran sodium sulfate; donepezil; electrogastrography; experimental pigs; gastric myoelectric activity; organ distribution; pharmacokinetics; video capsule enteroscopy

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MDPI and ACS Style

Bures, J.; Tacheci, I.; Kvetina, J.; Radochova, V.; Prchal, L.; Kohoutova, D.; Valis, M.; Novak, M.; Dolezal, R.; Kopacova, M.; et al. The Impact of Dextran Sodium Sulfate-Induced Gastrointestinal Injury on the Pharmacokinetic Parameters of Donepezil and Its Active Metabolite 6-O-desmethyldonepezil, and Gastric Myoelectric Activity in Experimental Pigs. Molecules 2021, 26, 2160. https://doi.org/10.3390/molecules26082160

AMA Style

Bures J, Tacheci I, Kvetina J, Radochova V, Prchal L, Kohoutova D, Valis M, Novak M, Dolezal R, Kopacova M, et al. The Impact of Dextran Sodium Sulfate-Induced Gastrointestinal Injury on the Pharmacokinetic Parameters of Donepezil and Its Active Metabolite 6-O-desmethyldonepezil, and Gastric Myoelectric Activity in Experimental Pigs. Molecules. 2021; 26(8):2160. https://doi.org/10.3390/molecules26082160

Chicago/Turabian Style

Bures, Jan, Ilja Tacheci, Jaroslav Kvetina, Vera Radochova, Lukas Prchal, Darina Kohoutova, Martin Valis, Martin Novak, Rafael Dolezal, Marcela Kopacova, and et al. 2021. "The Impact of Dextran Sodium Sulfate-Induced Gastrointestinal Injury on the Pharmacokinetic Parameters of Donepezil and Its Active Metabolite 6-O-desmethyldonepezil, and Gastric Myoelectric Activity in Experimental Pigs" Molecules 26, no. 8: 2160. https://doi.org/10.3390/molecules26082160

APA Style

Bures, J., Tacheci, I., Kvetina, J., Radochova, V., Prchal, L., Kohoutova, D., Valis, M., Novak, M., Dolezal, R., Kopacova, M., Rejchrt, S., Sestak, V., Knoblochova, V., Peterova, E., & Zdarova Karasova, J. (2021). The Impact of Dextran Sodium Sulfate-Induced Gastrointestinal Injury on the Pharmacokinetic Parameters of Donepezil and Its Active Metabolite 6-O-desmethyldonepezil, and Gastric Myoelectric Activity in Experimental Pigs. Molecules, 26(8), 2160. https://doi.org/10.3390/molecules26082160

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