The pharmacokinetic parameters and the effect of a single and repeated doses of memantine on gastric myoelectric activity in experimental pigs

Abstract

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).

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

“…Higher donepezil concentration in the pituitary compared the other brain regions suggests a role of the blood–brain barrier protection and active efflux mechanisms. In contrast to memantine, where the highest concentrations were found in the hippocampus and medulla [ 15 ], donepezil accumulated mainly in the medulla and medulla oblongata.…”

“…A markedly higher concentration of donepezil was found in the liver, which indicates a possible first pass effect, the proportion of active metabolite accounted for was 34%. In many aspects, the pharmacokinetic profile of donepezil follows similar patterns to memantine after intragastric administration [ 15 ], where highly perfused organs and organs of elimination (lung, kidney, liver) contained high concentrations of the drug. Donepezil also accumulated in the spleen.…”

“…Our original method of porcine surface electrogastrography (EGG) has already been published elsewhere [ 15 , 30 , 31 ]. Briefly, six active self-adhesive electrodes were placed on the upper part of the abdomen, the 7th electrode (basal) was placed to the left of the middle of the sternum.…”

“…Experimental dextran sodium sulfate (DSS)-induced injury can affect the function and morphology of different parts of the gastrointestinal tract, including the stomach, small intestine and large bowel [ 13 , 14 , 15 ]. Experimental pigs can be used in preclinical studies due to their similar gastrointestinal functions compared with humans [ 16 , 17 , 18 ].…”

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

“…Surface electrogastrography (EGG) is a non-invasive method for the assessment of gastric myoelectrical activity [ 27 , 28 , 29 , 30 , 31 , 32 ]. Our group has demonstrated that EGG is also reliable in experimental pigs [ 26 , 33 ]. Porcine surface EGG is fully comparable with that one recorded in healthy humans [ 34 ].…”