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I would like to ask for input on the following issue. During drug
development we have identified a compound for which it was
demonstrated that clinically relevant concentrations were able to
antagonize ligand-induced transcriptional activation by SXR (aka the
human PXR) in vitro ? As this nuclear receptor is a master regulator
of several phase I, phase II and drug transporters, it is conceivable
that antagonism could blunt induction responsiveness by SXR/PXR
regulated enzymes/transporters to endobiotic and xenobiotics.
How should these in vitro findings be interpreted and what further
pre-clinical studies (SXR humanized mice?) can be done to assess the
clinical relevance of the in vitro data?
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