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Question:
Anyone experienced substrate inhibition when determining metabolic
clearance?
I'm working on a compound "A" at 0.2 uM and 2 uM for metabolic
clearance using fresh hepatocytes (0-24 hr). The bi-exponential
decays were observed at both concentrations. We also found that the
compound is a mechanism-based inhibitor which may explain that the
phase 1 decay at 0.2 uM is faster than at 2 uM.
Which approach of the following is appropriate for the in vitro
intrinsic clearance calculation for bi-exponential decay compound ?
1) Dose/AUC
2) use the fast decay phase 1 half-life and apply to CL=0.693/t1/2 x
cell density?
3) use the traditional terminal half-life and apply to CL=0.693/t1/2
x cell density?
Thanks,
Valeria
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Hi Valeria,
It is quite obivous that at 0.2uM conc. you will find more decay, as
substrate quantity is less and enzyme availability is more.
You can use non-linear regression for Int. CLin calcaulation for bi-
exponential decay, considering initial value (0 min/hr) as 100%.
Jignesh
Torrent Research Centre
India
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