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Disposition of D2-antagonists in central nervous system
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (tPKPD)
2014 (English)Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Introduction: Antipsychotics used for the treatment of schizophrenia are often associated with the development of side effects linked to the alteration of physiological functions in some brain regions such as striatum and hypothalamus. The understanding of mechanisms driving the brain regional disposition of unbound antipsychotics will provide inside on target receptor – drug exposure relationship. Aim:  The aim of the project was to explore the disposition of two antipsychotics (paliperidone and haloperidol) in different regions of the brain as well as in the spinal cord with focus on the unbound drug concentrations. Materials and Methods:  To estimate the extent of the transport across the blood-brain barrier (BBB) antipsychotics were administered intravenously for four hours as constant-rate infusion. At steady-state conditions the brain regions (hypothalamus, cerebellum, cortex, striatum, hippocampus and brainstem) as well as the spinal cord were dissected, plasma and CSF samples were taken. Total brain to plasma concentration ratio was calculated for the regions (Kp,brain,i, where i is the region). For estimation of the fraction of unbound antipsychotics in homogenates of the regions of interest and plasma an equilibrium dialysis was performed. The unbound brain to plasma concentration ratio (Kp,uu,brain,i) was estimated. The concentration of drugs in all samples was measured using LC-MS/MS. Results and Conclusions:  The results revealed a significant difference (P-value<0.0001) in both  Kp,brain,i and Kp,uu,brain,i values for paliperidone and haloperidol. The fraction of unbound haloperidol in homogenate of brain regions and spinal cord was significantly different (P-value<0.0001). The fraction of unbound paliperidone in homogenate of brain regions and spinal cord was not significantly different. The highest Kp,uu,brain,i values were found for cortex and striatum, while the spinal cord was found to have one of the lowest Kp,uu,brain,i. The result from this study may support further research for understanding of the pharmacodynamic - pharmacokinetic relationship of typical and atypical antipsychotics. 

Place, publisher, year, edition, pages
2014. , 36 p.
Keyword [en]
blood-brain barrier, brain regions, brain tissue binding, D2-antagonists, drug disposition, Kp, uu, brain, i, unbound drug
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-230884OAI: oai:DiVA.org:uu-230884DiVA: diva2:742396
Subject / course
Educational program
Master of Science Programme in Pharmacy
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2014-09-01Bibliographically approved

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