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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
Pharmocokinetics
Challenge:
Design good physicochemistry into the molecules as early as possible.
What we know:
Physicochemistry correlates with ADME/tox.
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
Lipid bilayers: barrier for the entry of drugs into cells by passive diffusion
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
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:
Air-water interface: presence of multiple equilibria
Partitioning
Micellization
Air
Aqueous phase
Amphiphilicity is monitored through surface tension
Maximum pull technique:
Looking at the hydrophobic effect in action...
~1/Kaw
CMC
Slope=1/As=d/RTdlnc
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?
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
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
Spatial arrangement does matter
Propranolol Metoprolol
CNS+ CNS-
Solubility/hydrophobicity - antidepressants
Solubility/hydrophobicity - antidepressants
Solubility/hydrophobicity - antidepressants
Solubility/hydrophobicity – antidepressants
Compound Amitriptyline Protriptyline Doxepin
KAW 3527 2300 1182
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
Correlation between surface activity and PAMPA
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
Delta-8
• Multichannel microtensiometer
• 96-well compatible• Software controlled• Fully automated
Use of standard footprint 96-well plate
• 50 l per well• Optimized for surface
tension measurements
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)
Automated cleaning
• Electric owen heating up to 1000°C
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