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Proposed discussion points
The following points are proposed as starting points for
discussion. Of course, other points may be raised from the floor. Points are
presented here to allow time for more considered opinions to be formed before
being debated during the session. Anyone wishing to raise further points for
discussion should send them to
discussion@physchem.org.uk.
The importance of solubility in drug
discovery
Mainly the consequence of poor
solubility on other assays (bio-assays). I have been noticing that the Med
chemists don’t really care about poor solubility, because it is an issue
that in early development is taken care of (with miraculous formulations). I
am not concerned with solubility as such, but the consequences of a bad
solubility in the tests done at very early stages of the research that often
are decisive in the choice of proceeding or not with a compound.
The importance of solubility on
permeability
What happened to a permeability
measurement when the compounds assayed is not soluble in water? What really
mean the bell-shaped profile of permeability vs Log D often published? The
decrease of Permeability at logP/ D> ~5 (in these bell-shaped profile)
means a real decrease of Pe or is a consequence of poor aqueous solubility?
Why should a compound very lipophilic be less permeable (lower affinity
towards lipophilic environment)? Membrane retention? But in this case, we
have a problem of poor sink conditions (experimental set-up), and how well
can we extrapolate these poor sink condition to the GUT environment, when
the blood circulation creates a very big gradient in concentration?
The need of standardize PAMPA-Pe
values, at international level
Pe values obtained
with stirring conditions (which are used for more liphophilic compounds, due
to the unstirred water layer limitation) are always much higher that Pe
obtained in an assay without stirring (for the same compounds). So then the
question is; what is high permeability? Is 50 x10-6 cm/s high permeability
or low? If I use the stirring conditions I can measure Pe~ 4000x10-6 cm/s
for verapamil, while without stirring conditions is Pe~ 50 x10-6 cm/s.
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