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Blood-brain barrier transport and intra-brain distribution of memantine and donepezil in rats.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2016 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Introduction: Donepezil and memantine are CNS active drugs for treatment of Alzheimer´s disease. Knowledge on their blood-brain barrier (BBB) transport and the intra-brain distribution is important for understanding their target exposure.

Aim: The aim of this project was to determine the extent of donepezil and memantine BBB transport in the brain regions of interest (ROI) frontal cortex, parietal cortex, hippocampus, cerebellum and striatum and their intra-brain distribution in rats.

Materials and Methods: A combinatory mapping approach was used to assess the ratio between the steady state unbound concentrations in the brain interstitial fluid (ISF) and in plasma, Kp,uu,brain. The intra-brain distribution was evaluated via unbound volume of distribution in brain, Vu,brain (n=4) using brain slice method. Plasma protein binding at 500 ng/mL concentration was investigated by the equilibrium dialysis technique. The ratio between the total concentration in the brain ROIs and the plasma, Kp,ROI was assessed after intravenous 4 hour infusion of 3.34 mg/kg of donepezil (n=6) and 4.24 mg/kg of memantine (n=7). Bioanalysis was done by LC-MS/MS. One-way ANOVA was used for statistical analysis.

Results:  The Kp,brain assessed in the whole brain was 4.42±0.75 and 42.6±6.3 for donepezil and memantine, respectively with no significant differences in Kp,ROI. Both intra-brain distribution and plasma protein binding of donepezil and memantine were fairly similar as it was assessed by Vu,brain 23.2±1.8 and 28.7±2.3 mL/g brain and by the fraction of unbound drug in plasma 0.41±0.09 and 0.57±0.06, respectively. The Kp,uu,brain was 0.46±0.08 for donepezil and 2.60±0.39 for memantine.

Conclusions: The BBB transport of donepezil is limited while memantine is actively transported into the brain. The Vu,brain was higher than the ISF volume for both substances, which indicates intra-cellular distribution.

Place, publisher, year, edition, pages
2016. , 46 p.
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-298219OAI: oai:DiVA.org:uu-298219DiVA: diva2:945237
Educational program
Master of Science Programme in Pharmacy
Available from: 2016-07-01 Created: 2016-06-30 Last updated: 2016-07-01Bibliographically approved

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