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Transcript of Surface activity profiling: a novel physicochemical tool for the prediction of blood-brain-barrier...
![Page 1: Surface activity profiling: a novel physicochemical tool for the prediction of blood-brain-barrier permeation Paavo K.J. Kinnunen Helsinki Biophysics &](https://reader030.fdocuments.net/reader030/viewer/2022032516/56649c755503460f949290e7/html5/thumbnails/1.jpg)
Surface activity profiling:Surface activity profiling:a novel physicochemical tool for the prediction a novel physicochemical tool for the prediction
of blood-brain-barrier permeationof blood-brain-barrier permeation
Paavo K.J. KinnunenHelsinki Biophysics & Biomembrane Group
Institute of BiomedicineUniversity of Helsinki
Finland
![Page 2: Surface activity profiling: a novel physicochemical tool for the prediction of blood-brain-barrier permeation Paavo K.J. Kinnunen Helsinki Biophysics &](https://reader030.fdocuments.net/reader030/viewer/2022032516/56649c755503460f949290e7/html5/thumbnails/2.jpg)
Pharmocokinetics
Challenge:
Design good physicochemistry into the molecules as early as possible.
What we know:
Physicochemistry correlates with ADME/tox.
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Outline
1. Existing assays• logP, TPSA, CACO2, PAMPA,...
2. Amphiphilicity through surface activity• Model justification• Physicochemical parameters obtained
3. Overview on Delta-8 technology• Features and specifications
![Page 4: Surface activity profiling: a novel physicochemical tool for the prediction of blood-brain-barrier permeation Paavo K.J. Kinnunen Helsinki Biophysics &](https://reader030.fdocuments.net/reader030/viewer/2022032516/56649c755503460f949290e7/html5/thumbnails/4.jpg)
Lipid bilayers: barrier for the entry of drugs into cells by passive diffusion
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Ambiguous amphiphiles
In order to be useful as a drug a compound
• has to dissolve in water hydrophilicity required• has to permeate lipid bilayers lipophilicity required
•Hydrophilic part e.g. carboxylic acid derivatives•Lipophilic part e.g. hydrocarbon chain
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Air-water interface – a good model for lipid membranes
• Amphiphiles are strongly oriented in lipid membranes and in the air-water interface.
• Partitioning into both interfaces is mainly driven by the hydrophobic effect
Air/water interface: Phospholipid bilayer:
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Air-water interface: presence of multiple equilibria
Partitioning
Micellization
Air
Aqueous phase
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Amphiphilicity is monitored through surface tension
Maximum pull technique:
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Looking at the hydrophobic effect in action...
~1/Kaw
CMC
Slope=1/As=d/RTdlnc
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Compound structure must be optimized Compound structure must be optimized for optimum performance.for optimum performance.
Can surface activity profiling help?Can surface activity profiling help?
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Importance of the interfacial area
”common” phys-chem
100010000Kaw
>0.010.004CMC
14678As
Amphiphilicity profiling
4136TPSA
3.23.3LogP
308.4447.8MW
-+CNS
Phenyl
butazone
Hydroxyzine
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Prerequisites for passive permeation...
Nalbuphine Disopyramide
CNS + -
common physchem
MW 357 340
LogP 1.61 2.96
TPSA 73.2 59.2
surface activity profiling
KAW 461 195
AS(Å2) 65 129
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Spatial arrangement does matter
Propranolol Metoprolol
CNS+ CNS-
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Solubility/hydrophobicity - antidepressants
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Solubility/hydrophobicity - antidepressants
![Page 16: Surface activity profiling: a novel physicochemical tool for the prediction of blood-brain-barrier permeation Paavo K.J. Kinnunen Helsinki Biophysics &](https://reader030.fdocuments.net/reader030/viewer/2022032516/56649c755503460f949290e7/html5/thumbnails/16.jpg)
Solubility/hydrophobicity - antidepressants
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Solubility/hydrophobicity – antidepressants
Compound Amitriptyline Protriptyline Doxepin
KAW 3527 2300 1182
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CimetidineCaptopril
Sulpiride
Furosemide
Diltiazem
Sulfasalazine
Miconazole
Amitriptylin
IbuprofenPropranolol
Diphenhydramin
Acyclovir
Ranitidine
Atenolol
Paracetamol
Metoclopramid
0
20
40
60
80
100
-2,0 -1,0 0,0 1,0 2,0 3,0 4,0 5,0
Log P
Fra
cti
on
ab
so
rbe
d [
%]
Sulpiride
Furosemide
Diltiazem
Sulfasalazine
Miconazole
AmitriptylinPropranolol
Diphenhydramin
Acyclovir
RanitidineAtenolol
Paracetamol
Metoclopramid
CaptoprilCimetidineR2 = 0,77
0
20
40
60
80
100
-8,0 -7,0 -6,0 -5,0
Log Γmax [mol/m²]
Frac
tion
abso
rbed
[%]
dc
d
RT
c
Fraction absorbed: surface excess vs logP
Kiehm et al., AAPS, 2005
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Correlation between surface activity and PAMPA
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Literature for BBB-permeability
P. Suomalainen et al., Surface Activity Profiling of Drugs Applied to the Prediction of Blood-Brain Barrier Permeability. J. Med.Chem., 47:1738-1788,2004.
H. Fischer et al., Blood-Brain Barrier Permeation; Molecular Parameters Governing Passive Diffusion.J.Membr.Biol., 165:201-211, 1998
A.Seelig et al.A Method to Determine the Ability of Drugs to Diffuse Through the Blood-Brain Barrier.Proc. Natl.Acad.Sci., 91:68-72, 1994
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Delta-8
• Multichannel microtensiometer
• 96-well compatible• Software controlled• Fully automated
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Use of standard footprint 96-well plate
• 50 l per well• Optimized for surface
tension measurements
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The core: 8 high sensitivity microbalances
• Fixed to meet the positions of the wells in the 96-well plate
• Maximum pull force/du Nouy technique
• Probes instead of ring(s)
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Automated cleaning
• Electric owen heating up to 1000°C