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Hi All,
The in vitro EC50 (rat cell line) of few compounds against a CNS target is 300nM. The compounds were found to have descent activity in the relevant in vivo behavioral model across the dose ranges studied. In a separate rat PK study and also from analysis of samples from the behavioral assay, the in vivo unbound/free Cmax in brain tissue were found to be above 100nM for all the doses that were used in behavioral assays.
However there are few compounds from the same scaffold which are having similar EC50 values (around 300nM) and activity in in vivo behavioral models but the in vivo unbound Cmax in brain tissues are below 10nM for all the doses studied. What could be the potential reasons for this disconnect (apart from the possibility of in vivo generation of active metabolites!) ?
Thanks
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Hi Satya,
The other possibilities could be 1) difference in the receptor occupancy resulting into efficacy or 2) difference in the off rates of compounds from receptor of interest.
Raj
Rajinder Bhardwaj
DMPK
Lundbeck Research USA
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The following message was posted to: PharmPK
Hi Satya:
In addition to the 2 possibilities mentioned by Raj, diffusion in
brain tissue in vivo is slow and difficult. The unbound test compound
concentrations may be significantly different at action site and
measuring site. In general, in vitro information can be used as
reference only, because the physiological environments are completely
different between in vitro and in vivo studies. Demonstration of in
vivo efficacy is the key.
TK Chen
DMPK, Cylene Pharmaceuticals
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