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Distribution of unbound D2-antagonists in rat frontal cortex, striatum and corpus callosum; a pilot study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
2014 (English)Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
Abstract [en]

Introduction: To estimate the distribution of a drug in brain tissue, the unbound volume of distribution (Vu,brain) using the in vitro brain slice technique was employed. Previously, Vu,brain has only been calculated for the entire brain, and no consideration has been given to the different regions. Since the regions of the brain have different gene- and protein expression and neural cell representation, it is reasonable to presume that drugs entering the brain will have different distribution pattern in different regions. This may potentially affect the fraction of unbound drug in the distinct brain region and consequently the extent of pharmacological response of neuroleptics.

Aim: The aim with the study was to increase the knowledge about region specific distribution and binding of drugs through investigation Vu,brain of paliperidone, clozapine, olanzapine and quetiapine, in the cortex, striatum and corpus callosum of the rat using the brain slice method.

Materials and Methods: The study was conducted through the brain slice method. Six 300µm brain slices were incubated for five hours in a buffer containing the compounds (200 nM). At the end of the incubation, the buffer and brain slice samples were taken to analyse the concentration of compounds. The brain slices were either analysed as a whole or after micro-dissection to separate areas of frontal cortex, striatum and corpus callosum. The ratio between the amount of the drug in the brain slice and concentration in buffer was used to calculate Vu,brain.

Results: Vu,brain of all compounds were significantly higher in striatum compared to the whole brain, and Vu,brain in cortex was slightly elevated. There were no differences in Vu,brain of the studied drugs estimated using cassette and individual compound incubation approaches.

Conclusions:  This is the first effort to microdissect specific regions from the slice to calculate Vu,brain in different regions. The results show that there is a region-specific distribution of D2-antagonist, and this opens up opportunities for further studies and experiments.

Place, publisher, year, edition, pages
2014. , 21 p.
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-227770OAI: oai:DiVA.org:uu-227770DiVA: diva2:731079
Subject / course
Educational program
Bachelor of Science Programme in Pharmacy
Available from: 2014-09-09 Created: 2014-06-30 Last updated: 2014-09-09Bibliographically approved

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