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.

• Klíčová slova
• 6-O-desmethyldonepezil, dextran sodium sulfate, donepezil, electrogastrography, experimental pigs, gastric myoelectric activity, organ distribution, pharmacokinetics, video capsule enteroscopy,
• MeSH
• donepezil chemie   farmakokinetika   farmakologie   MeSH
• gastrointestinální trakt účinky léků   patologie   patofyziologie   MeSH
• indany metabolismus   MeSH
• kapslová endoskopie MeSH
• metabolom * účinky léků   MeSH
• migrující myoelektrický komplex * účinky léků   MeSH
• piperidiny metabolismus   MeSH
• prasata MeSH
• síran dextranu MeSH
• žaludek účinky léků   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 6-O-desmethyl donepezil MeSH Prohlížeč
• donepezil MeSH
• indany MeSH
• piperidiny MeSH
• síran dextranu MeSH

Current palliative pharmacotherapy of Alzheimer's disease based on the cholinergic hypothesis led to the development of four cholinesterase inhibitors. These compounds can bring prolongation of the symptom-free period in some patients. This is the first report directly comparing donepezil and rivastigmine plasma and brain levels in in-vivo study. Donepezil and rivastigmine were applied i.m. to rats; the dose was calculated from clinical recommendations. The samples were analysed on an Agilent 1260 Series LC with UV/VIS detector. An analytical column (Waters Spherisorb S5 W (250 mm × 4.6 i.d.; 5 μm particle size)) with guard column (Waters Spherisorb S5 W (30 mm × 4.6 mm i.d.)) was used. The mobile phase contained acetonitrile and 50 mM sodium dihydrogen phosphate (17:83; v/v); pH 3.1. The LLOQ in rat plasma was 0.5 ng/mL for donepezil and 0.8 ng/mL for rivastigmine, and the LLOQ in rat brain was 1.0 ng/mL for donepezil and 1.1 ng/mL for rivastigmine. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. Maximum brain concentration after i.m. administration was reached in the 36 (8.34 ± 0.34 ng/mL) and 17 minute (6.18 ± 0.40 ng/mL), respectively for donepezil and rivastigmine. The differences in brain profile can be most easily expressed by plasma/brain AUCtotal ratios: donepezil ratio in the brain was nine-times higher than in plasma and rivastigmine ratio was less than two-times higher than in plasma.

• Klíčová slova
• Acetylcholinesterase inhibitors, Alzheimer’s disease, Donepezil, HPLC, Rivastigmine,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Memantine, currently available for the treatment of Alzheimer's disease, is an uncompetitive antagonist of the N-methyl-D-aspartate type of glutamate receptors. Under normal physiologic conditions, these unstimulated receptor ion channels are blocked by magnesium ions, which are displaced after agonist-induced depolarization. In humans, memantine administration is associated with different gastrointestinal dysmotility side effects (vomiting, diarrhoea, constipation, motor-mediated abdominal pain), thus limiting its clinical use. Mechanism of these motility disorders has not been clarified yet. Pigs can be used in various preclinical experiments due to their relatively very similar gastrointestinal functions compared to humans. The aim of this study was to evaluate the impact of a single and repeated doses of memantine on porcine gastric myoelectric activity evaluated by means of electrogastrography (EGG). METHODS: Six adult female experimental pigs (Sus scrofa f. domestica, mean weight 41.7±5.0 kg) entered the study for two times. The first EGG was recorded after a single intragastric dose of memantine (20 mg). In the second part, EGG was accomplished after 7-day intragastric administration (20 mg per day). All EGG recordings were performed under general anaesthesia. Basal (15 minutes) and study recordings (120 minutes) were accomplished using an EGG stand (MMS, Enschede, the Netherlands). Running spectral analysis based on Fourier transform was used. Results were expressed as dominant frequency of gastric slow waves (DF) and power analysis (areas of amplitudes). RESULTS: Single dose of memantine significantly increased DF, from basic values (1.65±1.05 cycles per min.) to 2.86 cpm after 30 min. (p = 0.008), lasting till 75 min. (p = 0.014). Basal power (median 452; inter-quartile range 280-1312 μV^2) raised after 15 min. (median 827; IQR 224-2769; p = 0.386; NS), lasting next 30 min. Repetitively administrated memantine caused important gastric arrhythmia. Basal DF after single and repeated administration was not different, however, a DF increase in the second part was more prominent (up to 3.18±2.16 after 15 and 30 min., p<0.001). In comparison with a single dose, basal power was significantly higher after repetitively administrated memantine (median 3940; IQR 695-15023 μV^2; p<0.001). Next dose of 20 mg memantine in the second part induced a prominent drop of power after 15 min. (median 541; IQR 328-2280 μV^2; p<0.001), lasting till 120 min. (p<0.001). CONCLUSIONS: Both single and repeated doses of memantine increased DF. Severe gastric arrhythmia and long-lasting low power after repeated administration might explain possible gastric dysmotility side effects in the chronic use of memantine.

• MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• antagonisté excitačních aminokyselin aplikace a dávkování   škodlivé účinky   MeSH
• aplikace orální MeSH
• elektromyografie MeSH
• gastrointestinální motilita účinky léků   fyziologie   MeSH
• gastrointestinální nemoci chemicky indukované   diagnóza   patofyziologie   MeSH
• lidé MeSH
• memantin aplikace a dávkování   škodlivé účinky   MeSH
• modely nemocí na zvířatech MeSH
• Sus scrofa MeSH
• žaludek účinky léků   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté excitačních aminokyselin MeSH
• memantin MeSH