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I have a question regarding vehicle dependent changes in PK
parameters. I have seen differences in the volume of distribution
when i.v. dosing the same compound in two vehicle systems to rats.
With 5% cremophore EL 5% ethanol 90% PBS I get very reprodicible IV
kinetics with a Vss of 2000ml/kg, clearance 44ml/min/kg. I wanted to
use an alternative formulation without ethanol, so we used 50%
PEG400, 50% saline. This dropped the Vss down to 1293ml/kg and
clearance to 21ml/min/kg. What do the list members think is
happening? I wondered if the PEG vehicle was not mixing properly
with plasma, so reducing the Vd? Or is it that my Vd is being
artificially increased by the cremophore ethanol mix and the PEG
value is 'correct'? I would appreciate any thoughts on this.
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The following message was posted to: PharmPK
From your data, I think you might found that the plasma
much faster for the cremophor group than the PEG group, thus plasma
AUC is smaller, and clearnace, Vss is larger for the Cremophor group.
Vehicle dependent changes in PK parameters is very common. For
example, Doxil pk is significant different from doxorubicin pk.
For the explaination of your data, my two cents is:
1. Cremophor might sequester the drug and form micelles, thus it will
be cleared faster by the RES system due to the large size of the
2. Cremophor is a surfactant thus might enhance the penetration and
partition the drug to the tissue.
3. PEG 400 might enhance the solubility of the drug in the plasma,
and as you know, hydrophobic drugs tend to have larger volume of
distribution. I guess your drug is quite hydrophobic. But PEG 400 may
decrease the hydrophobicity of the drug.
I think it is not surprise that you get different Vss and clearance
for different formulations, and you can not say which one is right,
since vehicles may significantly change the pk character of the
Division of Pharmaceutics
the Ohio State University
Columbus, Ohio 43210
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