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I am curious to know whether the prediction of in-Vivo clearance from
in-vitro data is used as tool by drug discovery companies in hit- to-
lead or NOT?
many companies still do mouse liver microsomes but do not use the data
to shorlist compounds or do not use it for invivo dozing rather take
generic dose of 1mg/kg for I.v.
Are these predictions actually used in NCE research?
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Remember that to scale IVIVC you must ask the right question of the
right tools. It is not a formulae based approach... if that were the
case - everyone would be successful at it and we would not have 95%+
failure rates in discovery. Subcellular fractions predict only a
portion of the cleareance; even hepatocytes only are mildly predictive
of in vivo clearance becasue they cannot predict gut absorption,
distribution, non hepatic metabolism and elimination by non-hepatic
means, let alone sequestration in extravascular compartment...OH and
the list goes on. If one were to read the literature, one would get a
very contrarian view of things and so it is reasonable to expect that
scaling tools and heuristic approaches to simplification of the ADME
process can be achieved in a single species microsomal sample..
Sanjeev Thohan, PhD
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