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The following message was posted to: PharmPK
Dear all,
I 'm dealing with a group of compounds showing very high clearance
values
in the rat (100 ml/min/kg). Intrinsic Clearance (sometimes very low,
Hepatocytes) does not correlate with the in vivo data. Some compounds
produced still a relatively long terminal half-life (about 2 h).
There is
no instability in plasma. I'm looking for possible explanations,
since-according to theory- the plasma clearance is higher than
explainable
(by liver and kidney elimination).
Thank you very much!
Kind regards
Thomas
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The following message was posted to: PharmPK
Dear Thomas,
You should measure stability in freshly collected whole blood (not just
plasma) before you eliminate clearance in the circulation as a possible
explanation for total clearance in excess of hepatic blood flow. You
should also measure the blood to plasma ratio. If your compound has a
B/P ratio > 1, then your clearance in blood may actually be a more
reasonable value.
Peter Rix
Ligand Pharmaceuticals, Inc.
San Diego, CA
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Given that you have:
- high in vivo clearance
- low in vitro Clint
- a long t1/2
I'd consider the possibility that you have precipitation of drug
after iv administration...probably in the lung. Over time some
fraction of the precipitated drug slowly returns to circulation
producing a long terminal phase. As such, your measure of clearance
is actually CL/F.
Jeff Wald, PhD
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)