Surface activity profiling: a novel physicochemical tool for the prediction of blood-brain-barrier permeation

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Surface activity profilinga novel
physicochemical tool for the prediction of
blood-brain-barrier permeation

• Paavo K.J. Kinnunen
• Helsinki Biophysics Biomembrane Group
• Institute of Biomedicine
• University of Helsinki
• Finland

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Pharmocokinetics
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Outline

• Existing assays
• logP, TPSA, CACO2, PAMPA,...
• Amphiphilicity through surface activity
• Model justification
• Physicochemical parameters obtained
• 3. Overview on Delta-8 technology
• Features and specifications

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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
Air/water interface
Phospholipid bilayer

• Amphiphiles are strongly oriented in lipid
  membranes and in the air-water interface.
• Partitioning into both interfaces is mainly
  driven by the hydrophobic effect

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Air-water interface presence of multiple
equilibria
Air

Aqueous phase
Partitioning
Micellization
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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
Slope 1/Asdg/RTdlnc
CMC
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Compound structure must be optimized for optimum
performance. Can surface activity profiling help?
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Importance of the interfacial area
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Prerequisites for passive permeation...
Nalbuphine Disopyramide
CNS -
common physchem common physchem common physchem
MW 357 340
LogP 1.61 2.96
TPSA 73.2 59.2
surface activity profiling surface activity profiling 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
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Solubility/hydrophobicity - antidepressants
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Solubility/hydrophobicity antidepressants
Compound Amitriptyline Protriptyline Doxepin
KAW 3527 2300 1182
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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., 471738-1788,2004.
• H. Fischer et al.,
• Blood-Brain Barrier Permeation Molecular
  Parameters Governing Passive Diffusion.
• J.Membr.Biol., 165201-211, 1998
• A.Seelig et al.
• A Method to Determine the Ability of Drugs to
  Diffuse Through the Blood-Brain Barrier.
• Proc. Natl.Acad.Sci., 9168-72, 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 1000C