Transcript Confidential

Blood-Brain Barrier(BBB)
2013. 12. 13
Lee, Sang-Hwi
BBB (Blood brain Barrier)?
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전신 순환으로부터 뇌 순환 내로 대부분의 수동확산 되는 것을 차단하기 위한 특수한
폐쇄접합대.
뇌척수액(CSF)과 blood를 분리시키는 장벽으로 높은 선택적 투과성.
몸의 주요 조절중추를 세균 등과 같은 혈액으로 운반될 수 있는 병원체와 혈액 내의
잠재적인 위험물질로부터 격리시키는 역할
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BBB Fundamentals
perivascular neurons
surface area : ~12m2
TJ : tight junctions
AJ : adherens junctions
① Basal lamina(기저판): 아주 얇고 평탄한 층
MAO : monoamine oxidase
② Astrocyte(성상 교세표): 신경조직을 지지하는 신경아교를 이루는 세포
γ-GT : γ-glutamyl transpeptidase③ Pericyte(주피세포): 모세관의 전 단계,
Nature Reviews Drug Discovery 2007, 6, 650
세동맥의 기저막 바깥에 존재하는 수축력을 갖춘
길고 가느다란 특수한 세포.
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http://www.raptorpharma.com/science_neurotrans.html
http://www.youtube.com/watch?v=_e60_4ZV0zs
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Pathway across the BBB
Nature Reviews Neuroscience 2006, 7, 41
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Efflux ratio (ER)
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Generally, ER > 3 indicates significant efflux.
Pgp knockout mice also are used for verification of the in vitro conclusions.
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A survey of successful CNS drugs indicated
ER < 1 (22%), ER 1–3 (72%), ER > 3 (6%)
This suggests that many commercial CNS drugs are subject to low-to-moderate
levels of Pgp efflux that can be overcome with clinical dosing.
However, high Pgp efflux (ER > 3) is uncommon in commercial CNS drugs and
should be avoided.
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10.1.2 Brain Distribution Mechanisms
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Metabolic clearance
Plasma protein binding
Nonspecific binding to proteins and lipids in brain tissue
Clearance of compound from the extracellular fluid (ECF)
into the blood and cerebrospinal fluid (CSF)
reason?
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Plasma Protein Binding / Blood Brain Barrier
# Human Serum Albumin
-500~700 uM (35~50 mg/ml)
binds strongly to organic anions
(RCOOH, Phenols)
Basic / neutral drugs (minor)
60%
# AGP
15 uM (0.5~1.0 mg/ml)
Basic drugs (amines)
Hydrophobic drugs (steroids)
HSA : human serum albumin
hAAG : human
Bound drug can release in brain microvessel circulation in vivo much more than with in vitro assays.
Plasma protein binding is useful in retrospectively diagnosing the causes of low in vivo brain penetration.
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Blood
Brain
CSF
(거미막 융모)
(지주막하강)
(맥락총)
(경막)
(제4뇌실 맥락총)
(제3뇌실)
(제4뇌실)
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Blood cerebrospinal fluid barrier(BCFSB)
BCFSB
BBB
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http://en.wikipedia.org/wiki/File:NPH_MRI_272_GILD.gif
http://www.youtube.com/watch?v=SDMO4vYkqdg
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B/P, Log BB, Kp, and Kp,free Indicate the
Extent of Brain Distribution
# B/P = AUC
brain
/ AUC
plasma,
 log BB
• CNS drugs : B/P > 0.3 : minimum guideline for CNS discovery projects.
B/P < 0.1 : penetrate poorly into the brain
• C brain / C plasma : single time point or at Cmax
• C brain / C plasma : at steady state (also termed Kp)
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CNS Vs. Non-CNS drug
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10.3 Structure–BBB Penetration Relationships
< BBB rules >
v
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10.4 Structure Modification Strategies
to Improve Brain Penetration
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Reduce Hydrogen Bonds
 BBB permeation increase
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Increase Liphophilicity
 BBB permeation increase
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In Vitro Methods for BBB
1. PAMPA-BBB Method  BBB Permeability
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2. Lipophilicity  BBB Permeability and Brain Distribution
1 < log P < 3
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in vitro
BBB Permeability
Brain distribution (Brain/Plasma)
PAMPA-BBB
 passive BBB permeability CNS+, CNS-
Equilibrium dialysis
ΔLog P  Hydrogen bonding
IAM-HPLC column  passive diffusion
Surface activity
Cell-based in vitro methods
Microvessel endothelial cell permeability
Caco-2 method
MDR1-MDCKII  PgP efflux
TR-BBB and TM-BBB cell lines
Lipophilicity (Log D, Log P)
in vivo
BBB Permeability
Brain uptake index
Brain distribution (Brain/Plasma)
B/P ratio or Log BB
In situ perfusion, Log PS
Mouse brain uptake assay
Microdialysis method
Cerebrospinal fluid(CSF) method
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