Learning objectives
2024年11月20日 16:52
• Understand all main factors (/mechanisms) mechanisms governing BBB transport and intra -brain
(/CNS) distribution
○ Basic transport modes for BBB transport
▪ Simple diffusion
▪ Facilitated diffusion
▪ Fluid phase transport
: by vesicles formed out of the membrane
: requires energy and occurs into the direction of the brain
▪ Active transport
○ Specific transport modes for BBB transport
▪ Paracellular transport
▪ Transcellular transport
▪ Facilitated diffusion: helper molecule (transmembrane transport proteins ,channels)
▪ Influx transport
▪ Efflux transport
▪ RME (receptor-mediated endocytosis)
: in & out
: selective uptake of macromolecules
: RME has higher affinity and lower capacity than AME
▪ AME (adsorptive-mediated endocytosis)
: in & out
: involves endocytosis of charged substances in vesicles
: non-specific mechanism
: temperature dependent, saturable and ligand selective
▪ Pinocytosis
: in
: transport of extracellular fluid (ECF)
: hydrophilic
: very small vesicles
: non-specific uptake of ECF, non-competition, non-saturation
○ Main factors governing BBB transport
▪ Drug properties
: lipophilicity
: molecular size
: electrical charges
: dissociation constant
: affinity for carrier molecule
▪ Binding
: brain tissue binding
分区 Learning objectives 的第 1 页
, : brain tissue binding
: plasma protein binding
▪ BBB-specific factors
: opening of tight junctions
: expression of transporter
▪ Cerebral blood flow
▪ Disease and inflammation
○ Factors in CNS Drug Effects
▪ Protein plasma binding
▪ Cerebral blood flow
▪ Membrane transport
▪ Brain tissue binding
▪ Target occupancy
▪ PK/PD relationships
▪ Receptor theory
▪ Drug-drug interaction
○ Factors affect the PK of a drug in the CNS
▪ BBB Permeability: Determined by drug properties and transporter activity.
▪ Efflux Transporters: Reduce CNS concentrations by pumping drugs back into circulation.
▪ Metabolism: Both systemic (e.g., hepatic) and brain-specific metabolism affect drug levels.
▪ Plasma Protein Binding: Limits unbound drug available for CNS transport.
▪ CNS Drug Retention: Influenced by intracellular binding or sequestration.
• The significance of distinguishing between total and unbound drug concentration
○ Total concentration includes both protein-bound and unbound (free) drug fractions in the
plasma or tissue
○ Unbound concentration represents the pharmacologically active drug fraction capable of
crossing the BBB, binding to receptors, or exerting therapeutic effects
○ Significance: Total concentrations can overestimate drug availability, especially for highly
protein-bound drugs. Unbound concentrations correlate more directly with drug efficacy and
toxicity
• The importance of distinguishing between rate and extent of equilibration in brain distribution
○ Rate: the speed at which a drug reaches equilibrium between plasma and brain extracellular fluid
(ECF)
○ Extend: the degree to which a drug achieves equilibrium between plasma and brain ECF
○ Tools to Measure Rate and Extent of Equilibration
▪ Microdialysis: Measures real-time unbound drug concentrations in brain ECF, allowing
calculation of equilibration rate and extent.
▪ In Situ Brain Perfusion: Quantifies BBB permeability and transport kinetics, informing rate of
equilibration.
PK/PD Modeling: Mechanistic models link plasma and brain concentration profiles to CNS
分区 Learning objectives 的第 2 页
2024年11月20日 16:52
• Understand all main factors (/mechanisms) mechanisms governing BBB transport and intra -brain
(/CNS) distribution
○ Basic transport modes for BBB transport
▪ Simple diffusion
▪ Facilitated diffusion
▪ Fluid phase transport
: by vesicles formed out of the membrane
: requires energy and occurs into the direction of the brain
▪ Active transport
○ Specific transport modes for BBB transport
▪ Paracellular transport
▪ Transcellular transport
▪ Facilitated diffusion: helper molecule (transmembrane transport proteins ,channels)
▪ Influx transport
▪ Efflux transport
▪ RME (receptor-mediated endocytosis)
: in & out
: selective uptake of macromolecules
: RME has higher affinity and lower capacity than AME
▪ AME (adsorptive-mediated endocytosis)
: in & out
: involves endocytosis of charged substances in vesicles
: non-specific mechanism
: temperature dependent, saturable and ligand selective
▪ Pinocytosis
: in
: transport of extracellular fluid (ECF)
: hydrophilic
: very small vesicles
: non-specific uptake of ECF, non-competition, non-saturation
○ Main factors governing BBB transport
▪ Drug properties
: lipophilicity
: molecular size
: electrical charges
: dissociation constant
: affinity for carrier molecule
▪ Binding
: brain tissue binding
分区 Learning objectives 的第 1 页
, : brain tissue binding
: plasma protein binding
▪ BBB-specific factors
: opening of tight junctions
: expression of transporter
▪ Cerebral blood flow
▪ Disease and inflammation
○ Factors in CNS Drug Effects
▪ Protein plasma binding
▪ Cerebral blood flow
▪ Membrane transport
▪ Brain tissue binding
▪ Target occupancy
▪ PK/PD relationships
▪ Receptor theory
▪ Drug-drug interaction
○ Factors affect the PK of a drug in the CNS
▪ BBB Permeability: Determined by drug properties and transporter activity.
▪ Efflux Transporters: Reduce CNS concentrations by pumping drugs back into circulation.
▪ Metabolism: Both systemic (e.g., hepatic) and brain-specific metabolism affect drug levels.
▪ Plasma Protein Binding: Limits unbound drug available for CNS transport.
▪ CNS Drug Retention: Influenced by intracellular binding or sequestration.
• The significance of distinguishing between total and unbound drug concentration
○ Total concentration includes both protein-bound and unbound (free) drug fractions in the
plasma or tissue
○ Unbound concentration represents the pharmacologically active drug fraction capable of
crossing the BBB, binding to receptors, or exerting therapeutic effects
○ Significance: Total concentrations can overestimate drug availability, especially for highly
protein-bound drugs. Unbound concentrations correlate more directly with drug efficacy and
toxicity
• The importance of distinguishing between rate and extent of equilibration in brain distribution
○ Rate: the speed at which a drug reaches equilibrium between plasma and brain extracellular fluid
(ECF)
○ Extend: the degree to which a drug achieves equilibrium between plasma and brain ECF
○ Tools to Measure Rate and Extent of Equilibration
▪ Microdialysis: Measures real-time unbound drug concentrations in brain ECF, allowing
calculation of equilibration rate and extent.
▪ In Situ Brain Perfusion: Quantifies BBB permeability and transport kinetics, informing rate of
equilibration.
PK/PD Modeling: Mechanistic models link plasma and brain concentration profiles to CNS
分区 Learning objectives 的第 2 页
