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I have a general question and in need of professional PK input. We
are thinking about doing a PK study in mice in order to study a
potential drug-drug interaction between two compounds. Basically one
compound is a good substrate for a particular CYP450 isoform and the
other agent is a known inhibitor of that isoform.
Published studies in human liver microsomes have shown that the
metabolic oxidation of the substrate to an active metabolite is
significanly inhibited by this other compound.
My question is will a PK study in mice (assuming significant results)
be a useful study to perform and eventually publishable? Or do the
results in HLM incubations provide enough information that renders the
rodent study insignificant (not contributing any new information)
regardless of the outcomes.
Any feedback, suggestions or comments are welcomed.
Regards,
Alan
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Dear Alan
Quantification of active metabolite (presence and absence of inhibitor
drug) and studies with MLM (presence and absence of inhibitor drug)
would
add to the study. Further you can go for invitro-invivo correlation.
Hope this helps
Gurpreet Saini
Sr. Research Scientist
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Dear Alan,
Based on our experience, there is a reasonable possibility of
obtaining interesting results from the in vivo study. Small
differences in partition, sub-cellular distribution, and elimination
may reduce the level of interaction in vivo, relative to in vitro. I
would expect an effect to depend on the route of administration and
overall dose. Similarly, strain of mouse will influence the result -
certain outbreds will probably transform the compound faster than
common in breds for example and some mice will show the interaction
more intensely than others, if it is there.
Good luck and best regards
Michael Burnet
Michael Burnet Managing Director
Synovo GmbH
Paul Ehrlich Str. 15
72076 Tuebingen Germany
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Alan,
I don't think that it will be useful. The success of the study will
be dependent upon the compound being handled exactly the same in mouse
and man. That means, all elements of ADME, not just by certain CYP
isoforms. Reading between the lines, you have identified the CYP
isoforms in HLM that metabolize the drug that you are interested in.
Have you confirmed that the metabolism is the same in mouse
(metabolites formed and isoforms involved)?
If the study is intended to support a regulatory submission, then I
think that it will add little value to the Regulatory package. The
FDA will want either in vivo work in man or the HLM data may suffice
(depending upon what those results were).
If the intent of the study is for publication, the story may not be
complete without human data to show that the mouse can predict the
human situation. Without such information on your test compound (or
other compounds), the publication may not add that much to the
scientific community.
Sorry that I can't be more positive about such studies.
Regards
Mark
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Alan
There is a recent review article in Clin Pharmacol Therap
Mice as clinically relevant models for the study of cytochrome
P-450-dependent metabolism
Muruganandan and Sinal vol 83(6) p 818
Susan
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