Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE credits
Introduction: One of the main issues when designing drugs targeting the central nervous system (CNS) is penetration of the blood brain barrier (BBB). When studying the extent of drug transport across the BBB it is the unbound concentration, both in plasma and in the brain that is the most relevant for pharmacological effects. Therefore, the extent of unbound drug transport across the BBB is measured through Kp,uu, a ratio of brain interstitial fluid to plasma unbound drug concentrations.
Aim: The aim of the study was to determine whether there are any regional differences in the extent of drug transport across the BBB assessed by Kp,uu between the following regions: hypothalamus, cerebellum, cortex, striatum, hippocampus, brainstem and the spinal cord for four D2-antagonists (paliperidone, clozapine, olanzapine and quetiapine).
Methods: This was investigated through in vivo studies where drugs were administered to rats (n=4 per compound) via four hour intravenous constant rate infusion designed to achieve and maintain a steady state concentration. Blood, brain and CSF were sampled by the end of the infusion and stored at -80oCpending the analysis of total drug concentrations. Equilibrium dialysis in vitro studies were performed on brain homogenate of the regions of interest to determine the regional fraction of unbound drug. All samples were analysed by LC-MS/MS to measure the concentration of the drugs in brain, plasma and CSF matrices.
Results & Conclusions: It was found that there are significant differences in Kp,uu (p ≤ 0,01) between the structures for all the studied compounds. Noteworthy are the consistently high Kp,uu values for the hypothalamus as well as the low values in the spinal cord for paliperidone. The importance of unbound concentrations was also underlined as quetiapine had no significant regional differences when measuring total concentrations as opposed to when the unbound fraction had been accounted for. These results are a promising lead for further research in the area which may lead to a better understanding of the pharmacokinetics and pharmacodynamics of drugs targeting the CNS.
2014. , 28 p.