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Dear all,
Very naive question, whats the relevance of microsomal (or S9)
metabolic stability study in today's drug discovery? If the compound
is efficacious and safe (no other compararable candidate in
pipeline) should one reject it just because it is unstable in
microsome stability assay?
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The following message was posted to: PharmPK
In my experience, while microsomal and S9 assays can be helpful at
predicting what metabolic reactions are possible, they are quite often
misleading as to the extent of metabolism that will actually occur in
intact hepatocytes and/or in vivo. I have had compounds that are
metabolized rapidly in S9 assays show quite good stability in
hepatocytes and upon subsequent PK studies in vivo. I don't know how
others feel, but if your compound is efficacious in vivo and is safe,
I would certainly not reject it because of an in vitro microsomal
assay. If nothing else, you could take a look at the metabolites
generated in the in vitro assay, ask whether they are generated in
vivo, and perhaps even have them synthesized to evaluate toxicity
directly.
Noelle
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