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.

2nd Department of Internal Medicine Gastroenterology Charles University Faculty of Medicine in Hradec Kralove and University Hospital 500 03 Hradec Kralove Czech Republic

Animal Laboratory Faculty of Military Health Sciences University of Defence 500 01 Hradec Kralove Czech Republic

Centre of Biomedical Research University Hospital 500 05 Hradec Kralove Czech Republic

Department of Clinical Biochemistry and Diagnostics University Hospital Hradec Kralove 500 05 Hradec Kralove Czech Republic

Department of Neurology Charles University Faculty of Medicine in Hradec Kralove and University Hospital 500 03 Hradec Kralove Czech Republic

Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Charles University Faculty of Pharmacy 500 05 Hradec Kralove Czech Republic

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence 500 01 Hradec Kralove Czech Republic

The Royal Marsden Hospital NHS Foundation Trust London SW3 6JJ UK

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Birks J.S., Harvey R.J. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst. Rev. 2018;6:CD001190. doi: 10.1002/14651858.CD001190.pub3. PubMed DOI

Seltzer B. Donepezil: A review. Expert Opin. Drug. Metab. Toxicol. 2005;1:527–536. doi: 10.1517/17425255.1.3.527. PubMed DOI

Matsui K., Taniguchi S., Yoshimura T. Correlation of the intrinsic clearance of donepezil (Aricept) between in vivo and in vitro studies in rat, dog and human. Xenobiotica. 1999;29:1059–1072. doi: 10.1080/004982599237958. PubMed DOI

Atto R.A., Behnan A.B., Abachi F.T. In vitro kinetic study of donepezil N-oxide metabolites. Irq. J. Pharm. 2011;11:1–9.

Prvulovic D., Schneider B. Pharmacokinetic and pharmacodynamic evaluation of donepezil for the treatment of Alzheimer’s disease. Expert Opin. Drug. Metab. Toxicol. 2014;10:1039–1050. doi: 10.1517/17425255.2014.915028. PubMed DOI

Campbell N.L., Perkins A.J., Gao S., Skaar T.C., Li L., Hendrie H.C., Fowler N., Callahan C.M., Boustani M.A. Adherence and tolerability of Alzheimer’s disease medications: A pragmatic randomized trial. J. Am. Geriatr. Soc. 2017;65:1497–1504. doi: 10.1111/jgs.14827. PubMed DOI PMC

Valis M., Masopust J., Vysata O., Hort J., Dolezal R., Tomek J., Misik J., Kuca K., Karasova J.Z. Concentration of donepezil in the cerebrospinal fluid of AD patients: Evaluation of dosage sufficiency in standard treatment strategy. Neurotox. Res. 2017;31:162–168. doi: 10.1007/s12640-016-9672-y. PubMed DOI PMC

Thomson A.B. Small intestinal disorders in the elderly. Best Pr. Res. Clin. Gastroenterol. 2009;23:861–874. doi: 10.1016/j.bpg.2009.10.009. PubMed DOI

Soenen S., Rayner C.K., Jones K.L., Horowitz M. The ageing gastrointestinal tract. Curr. Opin. Clin. Nutr. Metab. Care. 2016;19:12–18. doi: 10.1097/MCO.0000000000000238. PubMed DOI

Hansen K.J., Wilson D.B., Craven T.E., Pearce J.D., English W.P., Edwards M.S., Ayerdi J., Burke G.L. Mesenteric artery disease in the elderly. J. Vasc. Surg. 2004;40:45–52. doi: 10.1016/j.jvs.2004.03.022. PubMed DOI

Bures J., Cyrany J., Kohoutova D., Förstl M., Rejchrt S., Kvetina J., Vorisek V., Kopacova M. Small intestinal bacterial overgrowth syndrome. World J. Gastroenterol. 2010;16:2978–2990. doi: 10.3748/wjg.v16.i24.2978. PubMed DOI PMC

Tai F.W.D., McAlindon M.E. NSAIDs and the small bowel. Curr. Opin. Gastroenterol. 2018;34:175–182. doi: 10.1097/MOG.0000000000000427. PubMed DOI

Tacheci I., Kvetina J., Kunes M., Edakkanambeth Varayil J., Ali S.M., Pavlik M., Kopacova M., Rejchrt S., Bures J., Pleskot M. Electrogastrography in experimental pigs: The influence of gastrointestinal injury induced by dextran sodium sulphate on porcine gastric erythromycin-stimulated myoelectric activity. Neuro. Endocrinol. Lett. 2011;32:131–136. PubMed

Lackeyram D., Young D., Kim C.J., Yang C., Archbold T.L., Mine Y., Fan M.Z. Interleukin-10 is differentially expressed in the small intestine and the colon experiencing chronic inflammation and ulcerative colitis induced by dextran sodium sulfate in young pigs. Physiol. Res. 2017;66:147–162. doi: 10.33549/physiolres.933259. PubMed DOI

Bures J., Kvetina J., Radochova V., Tacheci I., Peterova E., Herman D., Dolezal R., Kopacova M., Rejchrt S., Douda T., et al. The pharmacokinetic parameters and the effect of a single and repeated doses of memantine on gastric myoelectric activity in experimental pigs. PLoS ONE. 2020;15:e0227781. doi: 10.1371/journal.pone.0227781. PubMed DOI PMC

Kararli T.T. Comparison of the gastrointestinal anatomy, physiology and biochemistry of humans and commonly used laboratory animals. Biopharm. Drug. Dispos. 1995;16:351–380. doi: 10.1002/bdd.2510160502. PubMed DOI

Suenderhauf C., Parrott N. A physiologically based pharmacokinetic model of the minipig: Data compilation and model implementation. Pharm. Res. 1995;30:1–15. doi: 10.1007/s11095-012-0911-5. PubMed DOI

Gonzalez L.M., Moeser A.J., Blikslager A.T. Porcine models of digestive disease: The future of large animal translational research. Transl. Res. 2015;166:12–27. doi: 10.1016/j.trsl.2015.01.004. PubMed DOI PMC

Tiseo P.J., Perdomo C.A., Friedhoff L.T. Metabolism and elimination of 14C-donepezil in healthy volunteers: A single-dose study. Br. J. Clin. Pharm. 1998;46:19–24. doi: 10.1046/j.1365-2125.1998.0460s1019.x. PubMed DOI PMC

Heydorn W.E. Donepezil (E2020): A new acetylcholinesterase inhibitor. Review of its pharmacology, pharmacokinetics, and utility in the treatment of Alzheimer’s disease. Expert Opin. Investig. Drug. 1997;10:1527–1535. doi: 10.1517/13543784.6.10.1527. PubMed DOI

Amjad M.W., Alotaibi N.M. Formulation and in vitro characterization of donepezil-loaded chitosan nanoparticles. J. Pharm. Res. Int. 2020;32:57598. doi: 10.9734/jpri/2020/v32i1030488. DOI

Gu F.G., Fan H.M., Cong Z.X., Li S., Wang Y., Wu C.Z. Preparation, characterization, and in vivo pharmacokinetics of thermosensitive in situ nasal gel of donepezil hydrochloride. Acta Pharm. 2020;70:411–422. doi: 10.2478/acph-2020-0032. PubMed DOI

Sang Z.P., Wang K.R., Shi J., Liu W.M., Cheng X.F., Zhu G.F., Wang Y.L., Zhao Y.Y., Qiao Z.P., Wu A.G., et al. The development of advanced structural framework as multi-target-directed ligands for the treatment of Alzheimer’s disease. Eur. J. Med. Chem. 2020;192:112180. doi: 10.1016/j.ejmech.2020.112180. PubMed DOI

Darreh-Shori T., Meurling L., Pettersson T., Hugosson K., Hellström-Lindahl E., Andreasen N., Minthon L., Nordberg A. Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer’s disease following chronic donepezil treatment. J. Neural Transm. (Vienna) 2006;113:1791–1801. doi: 10.1007/s00702-006-0526-2. PubMed DOI

Tiseo P.J., Rogers S.L., Friedhoff L.T. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration. Br. J. Clin. Pharm. 1998;46:13–18. doi: 10.1046/j.1365-2125.1998.0460s1013.x. PubMed DOI PMC

Darreh-Shori T., Soininen H. Effects of cholinesterase inhibitors on the activities and protein levels of cholinesterases in the cerebrospinal fluid of patients with Alzheimer’s disease: A review of recent clinical studies. Curr. Alzheimer Res. 2010;7:67–73. doi: 10.2174/156720510790274455. PubMed DOI

Geerts H., Guillaumat P.O., Grantham C., Bode W., Anciaux K., Sachak S. Brain levels and acetylcholinesterase inhibition with galantamine and donepezil in rats, mice, and rabbits. Brain Res. 2005;1033:186–193. doi: 10.1016/j.brainres.2004.11.042. PubMed DOI

Groppa F., Coin A., De Rosa G., Granziera S., Alexopoulos C., Pamio M.V., Padrini R. Monitoring plasma levels of donepezil, 5-O-desmethyl-donepezil, 6-O-desmethyl-donepezil, and donepezil-N-oxide by a novel HPLC method in patients with Alzheimer disease. Drug Monit. 2016;38:108–113. doi: 10.1097/FTD.0000000000000246. PubMed DOI

Roman G.C., Rogers S.J. Donepezil: A clinical review of current and emerging indications. Expert Opin. Pharm. 2004;5:161–180. doi: 10.1517/14656566.5.1.161. PubMed DOI

Bures J., Jun D., Hrabinová M., Tacheci I., Kvetina J., Pavlik M., Rejchrt S., Douda T., Kunes M., Kuca K., et al. Impact of tacrine and 7-methoxytacrine on gastric myoelectrical activity assessed using electrogastrography in experimental pigs. Neuro. Endocrinol. Lett. 2015;36:150–155. PubMed

Bures J., Kvetina J., Pavlik M., Kunes M., Kopacova M., Rejchrt S., Jun D., Hrabinova M., Kuca K., Tacheci I. Impact of paraoxon followed by acetylcholinesterase reactivator HI-6 on gastric myoelectric activity in experimental pigs. Neuro. Endocrinol. Lett. 2013;34:79–83. PubMed

Kopacova M., Tacheci I., Kvetina J., Bures J., Kunes M., Spelda S., Tycova V., Svoboda Z., Rejchrt S. Wireless video capsule enteroscopy in preclinical studies: Methodical design of its applicability in experimental pigs. Dig. Dis. Sci. 2010;55:626–630. doi: 10.1007/s10620-009-0779-3. PubMed DOI PMC

Tacheci I., Kvetina J., Bures J., Osterreicher J., Kunes M., Pejchal J., Rejchrt S., Spelda S., Kopacova M. Wireless capsule endoscopy in enteropathy induced by nonsteroidal anti-inflammatory drugs in pigs. Dig. Dis. Sci. 2010;55:2471–2477. doi: 10.1007/s10620-009-1066-z. PubMed DOI

Zdarova Karasova J., Sestak V., Korabecny J., Mezeiova E., Palicka V., Kuca K., Mzik M. 1-Benzyl-4-methylpiperidinyl moiety in donepezil: The priority ticket across the blood-brain-barrier in rats. J. Chrom. B. 2018;1092:350–358. doi: 10.1016/j.jchromb.2018.06.034. PubMed DOI

Tveden-Nyborg P., Bergmann T.K., Lykkesfeldt J. Basic & clinical pharmacology & toxicology policy for experimental and clinical studies. Basic Clin. Pharm. Toxicol. 2018;123:233–235. PubMed

Explanatory Report on the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (ETS 123) Council of Europe; Strasbourg, France: 2009.

Kilkenny C., Browne W.J., Cuthill I.C., Emerson M., Altman D.G. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8:e1000412. doi: 10.1371/journal.pbio.1000412. PubMed DOI PMC

The Effect of Tacrine on Functional Response of the Lower Oesophageal Sphincter Assessed by Endoscopic Luminal Impedance Planimetry in Experimental Pigs

The effect of single and repeated doses of rivastigmine on gastric myoelectric activity in experimental pigs

Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice

Dextran Sodium Sulphate-Induced Gastrointestinal Injury Further Aggravates the Impact of Galantamine on the Gastric Myoelectric Activity in Experimental Pigs