血脑屏障Blood-Brain Barrier.ppt

Blood-Brain Barrier Sep, 20, 2010 Fei sun Blood-Brain Barrier introduction What is the Blood Brain Barrier BBB permeation mechanisms Restrictive physicochemical characteristics High efflux activity and uptake transport Brain distribution mechanisms Metabolic clearance Plasma protein binding  Nonspecific binding to proteins and lipids in brain tissue  Brain–CSF Barrier Interpreting Data for Brain Penetration The limitation of B/P Papp, PS, and t1/2eq.in Indicate the Rate of BBB Permeability Effects of Brain Penetration Structure–BBB Penetration Relationships  * Phosphatidylserine mechanisms limit the access of compounds to brain cells by affecting the distribution of compound to or within the brain Bound drug can release in brain microvessel circulation Summarize the major mechanisms affecting brain exposure The most commonly used brain penetration data is B/P; its log is Log BB. B/P is is calculated from various data: B/P 0.3 is used as a minimum guideline for CNS discovery projects. yet some commercial CNS drugs have B/P 0.1. BBB penetration is necessary for CNS drugs.10 However, drugs for therapy in peripheral tissues may cause side effects in the brain; therefore, it is desirable that they have minimal penetration into the brain. It may be possible to reduce CNS side effects of peripheral drugs by making structural modifications that reduce the brain penetration. key structural properties for discovery of CNS drugs A set of physicochemical BBB rules was first proposed by Pardridge Another set of BBB rules was compiled by Clark and Lobell Structure Modification Strategies to Improve Brain Penetration Reduce hydrogen bonds to improve BBB permeation Increase Lipophilicity to improve BBB permeation It should be noted that increasing lipophilicity to improve BBB permeation also can have a negative effect on BBB penetration. According to the “pharmacokinetic rule,” increasing lipophilicity also increases nonspecific binding in the brain, reduces fre