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Dear all
I'd like to know what isoforms of CYP450 are expressed in mouse
hepatic microsomes in order to inhibit them specifically with compound
inhibitors.
Can someone give me some information about that ?
Any literature references would be very helpful.
Thanks a lot in advance
Regards
Florence
Florence Leroux, Pharm, PhD, IR Inserm
INSERM U761 Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
1, rue du Pr Calmette, 59019 Lille Cedex
florence.leroux.-a-.pasteur-lille.fr
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The following message was posted to: PharmPK
Hi Florence,
You may find relevant information ...in the PharmPK archives.
Furthermore, have a look at the discussion which has been started
earlier this week, under the title
"CYP2C8 mediated drug metabolism in animal models".
I would also suggest to have a look at:
Bogaards JJ, Bertrand M, Jackson P, Oudshoorn MJ, Weaver RJ, van
Bladeren PJ, Walther B
Xenobiotica. 2000 Dec;30(12):1131-52
Determining the best animal model for human cytochrome P450
activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey
and man
Hope that helps.
Frederic MASSIERE, Oroxcell
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The following message was posted to: PharmPK
Hi Florence,
Sorry for being so blunt, but: Why do you need to look at it?
If you are interested in human DDI prediction, the only regulatorily
accepted model is using pooled human liver microsomes anyway. (see
(Draft)
Guidance on Drug interaction studies, FDA 2006)
Or are you are interested in understanding mouse NCE metabolism/ in vivo
PK/Tox findings?
How about using material from CYP knockout mice?
Reference:
"In vitro metabolism of styrene to styrene oxide in liver and lung of
CYP2E1
knockout mice"
CARLSON Gary P.
Journal of toxicology and environmental health. Part A (J. toxicol.
environ. health, Part A)
2003, vol. 66, no9, pp. 861-869 [9 page(s) (article)] (1 p.1/4)
(Maybe it is also worth looking at isoform specific inhibition through
the
use of antibodies instead of chemical inhibitors?)
Mouse CYP inhibition is probably not of prime regulatory interest, thus
there is (at least to my knowledge) comparatively little need for
information on specific "validated" chemical inhibitors. You may have
to
piece the right substrates and possible inhibitors out of the
literature.
Here is one reference that might help,:
"Competitive inhibition of coumarin 7-hydroxylation by pilocarpine and
its
interaction with mouse CYP 2A5 and human CYP 2A6"
T. Kinonen, M. Pasanen, J. Gynther, A. Poso, T. Jaervinen, E. Alhava,
and R.
O. Juvonen
Br J Pharmacol. 1995 November; 116(6): 26252630
And finally (although I am not sure how helpful it is for answering the
question of mouse-isoform specific chemical INHIBITORS)
"Metabolism of human cytochrome P450 marker substrates in mouse: a
strain
and gender comparison"
LOeFGREN S. ; HAGBJOeRK A.-L. ; EKMAN S. ; FRANSSON-STEEN R. ;
TERELIUS Y. ;
Xenobiotica
2004, vol. 34, no9, pp. 811-834
Best regards,
Constance
DMPKORE
Dr C Hoefer
Lannerstrasse 8
D-85057 Ingolstadt
Germany
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Dear Constance
Dear Frederic
Thanks a lot for your help.
Constance asked why we are interesting in mouse microsomes. The reason
is that one of our best compounds failed to achieve enough plasma
concentration in the mouse, the pharmacological model, to induce the
expected activity. Consequently we want to investigate deeper its P450
metabolism in the mouse. The results could also help us to find an
inhibitor that could be co-administered to quickly obtain a proof of
concept in the mouse.
Sincerely
Florence
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