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We are working with two discovery compounds which were shown to be
stable in rat liver microsome and hepatocytes, with high permeability
across Caco-2 cells, but with poor oral bioavailability in rats (one
cannot be calculated and the other <10%).
In order to assess gut absorption versus in vivo liver metabolism, we
repeated the oral dosing in rat and collected blood samples from the
portal vein. Cmax values were 62 and 24 times higher than those
determined previously when samples were collected from jugular vein,
while Tmax remained the same. Can we conclude in this case that the
in vitro metabolism study results were not predictive and high first
pass metabolism in liver was indeed the reason for the poor oral
bioavailability?
In addition, can the liver extraction ratio be derived as
E=(Cportal - Cjugular)/Cportal
with the assumption that Cjugular is representative of the plasma
concentration in the hepatic vein and no consideration for the portal
vein blood volume or blood flow rate versus the systemic blood volume
and blood flow?
Any input is greatly appreciated.
CJ
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CJ,
Have you ruled out the role of efflux transporters?
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The following message was posted to: PharmPK
Hi,
Here bellow 3 different ideas which may perhaps explain why in spite
of a high stability in hepatocyte and high permeability, the oral
bioavailability was low:
1. Stability testing in hepatocytes: did you run the in vitro studies
using suitable concentrations so that the metabolism was not saturated?
2. Dosing rats and collection from portal vein which provides 62 and
24 times increase in Cmax compared to jugular concentrations after
oral administration: check whether the compound precipitates in the GI
tract after oral dosing versus solution perfusion in the GI tract
during blood collection from portal vein.
3. Bile excretion: Do you have any idea about exertion rate in bile?
Hope that this may help
Jean
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The following message was posted to: PharmPK
Have you studied solubility and efflux transporters ?
Pr G. Ubeaud-Sequier
professor of pharmacokinetis
CNRS 7175, University Louis Pasteur
Faculty Pharmacy, Strasbourg France
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Did you consider clearance by non-CYP mediated mechanisms?
Ravi
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