How the Rate of Passive Transport (Permeability) Correlates to the Extent of Transport (Kp,uu) across the Blood-Brain-Barrier
Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
Introduction: The success rate in CNS drug development has been rather low in comparison to non-CNS drugs. This is among other reasons due to the complexity of the brain and its physiological barrier, the blood-brain-barrier (BBB), especially the presence of active transporters (efflux and influx) in the BBB. Another reason for the low success rate is the lack of good methods for screening of new CNS compounds. Screening has been based on measuring permeability in i.e. Caco-2 cells and total concentration ratio between brain and plasma (logBB). However, this approach has been questioned since logBB is confounded by non-specific binding to brain tissue, plasma protein binding, active transport and metabolism. Historically, permeability has been considered to be the most important factor. A more relevant parameter for pharmacological activity is the unbound brain-to-plasma concentration ratio (Kp,uu). However, the relation between permeability and Kp,uu is not investigated.
Aim: To investigate the relationship between rate (permeability) and extent (Kp,uu) parameters of drug transport across the BBB.
Materials and Methods: Extent and physcico-chemical properties data for 41 compounds were extracted from earlier studies and permeability data for 30 compounds were obtained from pION Inc. Standard regression analysis was used to assess the correlation between different parameters. Simca P+ was used for PLS-regression analysis.
Results: The investigation of the relationship between permeability (rate) and extent across the brain shows that there is no correlation between these two parameters.
Conclusions: This study has contributed to further increasing the understanding of the parameters in question. Because of the lacking relationship between rate and extent sceening of new CNS compounds cannot be based on permeability.
Place, publisher, year, edition, pages
2012. , 25 p.
IdentifiersURN: urn:nbn:se:uu:diva-185454OAI: oai:DiVA.org:uu-185454DiVA: diva2:571822
Subject / course
Master of Science Programme in Pharmacy
Hammarlund-Udenaes, Margareta, Professor
Bengtsson, Jörgen, Director of Studies