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The following message was posted to: PharmPK
Dear all,
I am studying the metabolism of a drug in c-DNA
expressed recombinant cytochromes P450 enzyme models,
and I am going to use one of the two approaches most
commonly used to scale these results to human liver
microsomes. The first one is the use of the relative
activity factor (RAF) proposed by crespi et al 1995,
and the second one is to multiply the rate of
metabolite formation in pmole/min/pmole recombinant
CYP by the relative abundance of this CYP isoform in
the population. I have two questions to ask :
1- What are the limitations of each approaches and
which one is more convenient with the requirements of
the drug regulatory authorities for IND application of
a new drug.
2-If we used the relative content approach to
calculate the relative contribution of different CYP
isoforms in the metabolism of the drug, is it more
appropriate to use literature data from large
population to scale up our results or we can use the
content of these isoforms in our pool of human liver
microsomes (10-20 livers)that we used to determine the
intrinsic clearance of the drug.
Could you supply me with references about the relative
content of the Cytochromes CYP2B6, CYP3A4 and CYP1A2
in human liver.
Thank you for your cooperation
Youssef Hijazi
H=F4pital neurologique et neurochirurgicale
UNITE DE PHARMACOLOGIE CLINIQUE
Service Pharmaceutique
d=E9partement de dosage de m=E9dicaments et de Pharmacocin=E9tique
B.P. Lyon Montchat 69394 Lyon Cedex 03-FRANCE
Tel: 04 72 35 72 45
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