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A compound which its in vitro data got from metabolic stability
study is:
in vitro t1/2: 2.1 min;
in vivo intrinsic clearance is about 500 mL/min/kg;
systemic clearance is 60 mL/min/kg
predicted maximum oral F% is only 12%.
What I used is rat liver microsomes
But we also have done IV/PO experiments in rats of this compound
and its PK parameters are very good (F%>60%, t1/2 is about 4 hrs for
PO and 6 hrs for IV, systemic clearance is about 20 mL/min).
So we can see that there are large contradictions between the in
vitro and in vivo data. Does anyone ever meet this phenomenon and who
can tell me how to explain it? Thanks!
Best wishes,
Jian wang
Dept. DMPK of Hutchison Medipharma in Shanghai
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The following message was posted to: PharmPK
Dear Jian Wang,
Did you include plasma protein binding in your calculations? Usually
correction using fraction unbound goes too far and underestimates
hepatic extraction.
Regards.
Ted
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Could you try to correct for both protein and microsome binding, the
formulation is:
Cl=(Q*CLint*fuplasma/fumicrosome)/(Q+CLint*fuplasma/fumicrosome)
Alternatively, measure in vitro hepatocyte clearance and scale the Cl.
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Usually in vitro data can only be used to predict in vivo Kinetic data.
It can never be automatic because of the complex processes in which
drugs go through in the blood stream.
Your data might be correct and may only require biopharmaceutic
explanation.
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Dear Lu
Considering fumic and fu can potentially improve the hepatic
clearance prediction; however as the liver well-stirred model is
developed with respect to blood, the blood related data should be
used (fub instead of fu), please see: http://dmd.aspetjournals.org/
cgi/content/full/35/3/501.
Also, for a more detailed explanation of in vitro-in vivo
extrapolation (IVIVE) approach, among many other references, you may
find the following paper useful. http://dx.doi.org/
10.1080/00498250600683197 .
Regards
Masoud
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Jamei,
Yeah I agree that fub should be used. Thank you for the input and the
papers.
--
Dan Lu, Ph.D. Research Scientist I
Roche Palo Alto
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Nice suggestions all, but contradictions in vitro and in vivo are not
surprising. Are you sure that the half life in your microsomal
incubations is not due to non-metabolic reasons, i.e. non CYP related
or NADPH related. Also what are the phys chem props of the compound
and could you be seeing an accumulation in the lipid, protein of the
incubation that does not allow full recovery of the analyte.
Troubleshoot the assay for your microsomes by investigating different
protein (and hence lipid) contents as well as non-NADPH and NADH-
containing controls, if you want to understand the disconnect. Also
what were the Vss values, if you're highly distributed are you
getting the compound to the clearance organ? Are you sure that
hepatic clearance is the main route of elimination in vivo?
remember the determinants of the IVIVC for microsomes to in vivo.
Good luck.
Sanjeev Thohan, PhD
Director, DMPK
Exelixis, Inc
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