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Hi,
I am working on a highly insoluble NCE (Aqueous solubility less than
1nanogram /mL at pH 7.4). The oral bioavailability of the compound is 50 %
in mice. For determining Plasma Protein binding, I tried ultrafiltration
method. But the concentrations in plasma water were below the limit of
quantitation ( 20 ng/mL on HPLC). More over It is not possible to prepare
aqueous calibration standards for analysis. Also I am facing difficulty in
spiking this compound to liver microsomal cocktail for accessing the
metabolic stability and fingerprinting the metabolites. Even addition of
Methanol/DMSO upto 2% for spiking could not solve the problem.
I will appreciate if someone with experience can suggest to handle such
compounds in pre-clinical development
Jyoti Paliwal Ph. D.
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Hello
Inspite of having such a low aqueous solubility the bioavailability of 50% is
something interesting. It clearly shows that apart from aqueous solubility a
selective carrier system or improved dissolution by bile components might be
playing a role. I was wondering if you can dissolve your compound in bile
(surfactants which might improve the aqueous solubility) and then use that for
your studies. Of course you might have to run control to determine the effect
of bile components in drug metabolism. But since in vivo bile is a natural
substance I think you can use it. I am not aware of any references in this
direction. Perhaps somebody could comment on this. I am presuming that your
drug is basic in nature. For binding studies I think radiolabeled drug will be
more promising that cold drug.
Atul
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)