Dear All:Back to the Top
We dosed an anti-cancer compound for 5 days (40 mg/kg, PO, QD) to mice and
found a 75% decrease in AUC (Day 1 vs. Day 5 comparison). This was done
to better select a compound for future pharmacolgical evaluation in a mouse
anti-tumor model that runs for a month. How should we proceed? It may be
"THE END" for this compound if it fails the efficacy trial in mouse, but
the broader question is that does animal P450 induction correlate with the
human situation? I am of the opinion that it is not, but I want to hear
what the experts have to say.
Hi Garcia,Back to the Top
I have seen several times that compunds have rodent specific CYP P450
induction, which does not result in induction in human. However, I am not
sure if this is always the case. One way to screen for this correlation is
by in vitro induction assays using rodent and human hepatocytes.
Pfizer Global Research & Development
I might not be an expert on this issue. But you may be right as I have seenBack to the Top
there is difference in induction in the two models. The female vs male
model may have differences in induction with respect to environmental
exposure, diet and starvation.
Further it is important to know, whats the half life of your drug?
secondly, what all enzymes are involved in the metabolism. Phase I only or
Garcia,Back to the Top
Increase in AUC that you observed may not be related
to P450; it may be related to reduce/impair clearance
due to drug toxicity. What is the mechanism of action
of your drug? Is it possible that your drug caused
hepatobiliary (or renal) toxicity? Do you any idea on
dose linearity of this compound? I have seen this
phenomenon with some of the anticancer compounds that
I have worked with.
Dear Anis,Back to the Top
Is this rodent specific CYP P450 induction true for a particular class of
compounds, or it is at random.
Hope you can throw some more light on this.
Ranbaxy Research Laboratories
New Delhi. India
There is a wide inter species variation in the expression of CYP450Back to the Top
isozymes. I think the comment of Anis is not specific for a class of
compounds acting as inducers but species specific induction of CYP450
isozymes. To quote an example Rifampicin is a inducer of CYP3A4 in
humans but not in rats.
So far this is only mouse specific induction observed (based on theBack to the Top
decrease in AUC). It is not true for all compounds from this class and was
observed only for 3 compounds so far. No human data has been generated. I
hope this answers your question.
Dear Rostam:Back to the Top
Sorry if I was unclear in my earlier message. There was a 75% DECREASE in
AUC on Day 5 compared to the AUC on Day1.
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