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Dear Forum
We are working on the pharmacokinetic drug-drug interaction in animal
models.
Following doubts i want to clear for the future studies.
1) Is the rat is good models for study of CYP2C8/9 mediated drug-drug
interaction?
2) For in-vitro study inhibition of CYP2C8/9 can we use rat microsomes?
3) Which animal model we should use to study the CYP2C8/9 mediated
drug metabolism?
As some of the studies like Paclitaxel and amiodarone was carried out
in rat microsomes and both drugs are metabolising by CYP2C8 enzyme.
Also Rabbits is good animal models for the study of CYP2C8/9, CYP3A4
inhibition and induction mechanism of drug-drug interaction.
If any reference is there kindly provide us. It will be great help for
our academic institute
Thank you
NIL
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The following message was posted to: PharmPK
NIL,
By strict definition, rats will metabolize a drug by a CYP2C8-mediated
mechanism since CYP2C8 is a human isoform (as is CYP2C9). Each
isoform (human or animal), will have it's own unique substrate
specificity. The nomenclature is based on sequence similarity and not
on enzyme activity. Therefore, a drug that is metabolized by CYP2C8
in humans may not be metabolized by a member of the CYP2C family in
animals.
The following websites will provide the information that you need on
nomenclature:
http://www.cypalleles.ki.se/
http://drnelson.utmem.edu/CytochromeP450.html
Animals have very rarely been used as models for drug-drug interaction
studies. This is due to the difference in enzymology between humans
and animals which may mean that the drugs are metabolized differently
or that the drugs are metabolized to the same metabolites but by
different pathways.
I wish that I could have been more positive in my response to you. If
animal models could be used to predict human DDIs my job would be so
much easier.
Regards
Mark Milton
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Re: CYP2C8 mediated drug metabolism in animal models
Dear Nil
I agree with Mark that if you want to study the CYP2C8 drug -drug
interaction. rat is not a good model becuase 2C8, 2C9 and 2C10 is the
human CYP isoforms and these isoforms do not exist in animal. Try
using human liver microsomes or recombinant CYPs for in vitro study.
I have tried the inhibitory effct of some chemicals on CYP3A-
mediated testosterone hydroxylationusing human microsomes and rat
microsomes. The resultf were quite different between human and rat
micromes. Weak inhibitor obtained from human microsomes may act as
strong inhibitor when using rat microsome as the enzymes source .
Regards,
Wichittra
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The following message was posted to: PharmPK
Dear Wichittra,
Which Recombinant Cyp(company) have you used.
Have you faced issues of stability.
Cheers
Praveen
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