Back to the Top
The following message was posted to: PharmPK
Hi, All:
We have a drug that maybe has inhibition or induction on CYP2C
or CYP3A according to the results of rat and dog experiment. And we
have done the inhibition experiment of human CYP450 enzymes in vitro
but found no inhibition. So do we need to do the inhibition
experiment of rat and dog CYP450 enzymes? Because we know that the
induction and inhibition on CYP450-dependent monooxygenase system
have species variation, even we do the rat and dog P450 experiment
and get the results we want, I think we can not say that it is the
inhibitor or inducer of CYP450s. So is it nesessary to do the
experiments?
I have another question is if the drug is a inducer of
CYP450s,what do we need to do? I know how to do the induction
experiment on animals, but I don't know how to do it on humans. Can
anyone tell me? Thanks!!
Jian wang
Dept.Pharmacology
Hutchison medipharma Limited
Back to the Top
The following message was posted to: PharmPK
Dear Mr Jian Wang,
It's not easy to answer, due to lack of information about all the
context of your research.
Nonetheless, I believe you do not have to do any further CYP inhition
experiment on animal enzymes, unless you want to rationalize PK data in
those species.
For preclinical induction studies, you may run experiments in human
hepatocytes.
Hope that helps.
F. Massiere
Back to the Top
hi jian wang,
for induction studies, in vitro, you could try BDGentest fresh human
hepatocytes. try http://bdbiosciences.com
they will also provide you with the necessary protocols.
i hope this helps.
regards,
mario shields.
Back to the Top
Hi, Jian,
It is difficult to say continuing the experiments in other species
unless you go further studies. It also depends on the assay method
and test system you selected in your studies, especially for
inhibition study.
For in vitro induction study, you can use human hypatocyte from
commercial resource, and detect the RNA , protein level, and enzyme
activity of your interested P450. Or you can use a PXR reporter gene
assay system for CYP3A4. The former method is more reliable,
according to my experience.
Lucy
--
Hong(Lucy) Lu
Sr. Research Associate
Synta Pharmaceutical Corp.
Lexington, MA
Back to the Top
The following message was posted to: PharmPK
Hi,All:
I am very glad to see the responses you give to me.
The problem I meet is:We have done the human P450 inhibition
experiment in vitro before and the result is negative.But recently,we
did the drug interaction experiments with taxol and carboplatin on
rats and dogs.In these experiments,we found that it can reduce male
rats' clearence of taxol,so I think it maybe a inhibitor of CYP3A.So
compared with the results of human P450 inhibition experiment in
vitro,I don't know if I need to do further studies on it or not?And I
think even if we do the rats and dogs P450 inhibition experiments in
vitro,the results can only be used to explain the phenomenon appeared
in rats and dogs.We can not say whether it will appeared in humans or
not. The drug we studied is a anti-tumor drug and we want to apply it
to FDA to go on clinical phase 2 study.
About the induction study,who can give me some references
because I have very poor experience on it?Thanks!
Back to the Top
The following message was posted to: PharmPK
Wang Jian,
Depending on the dosing regimen the carboplatin effect may not be
due to acute enzyme inhibition but could be due to down-regulation
of enzymes. Cisplatin causes testicular feminisation in rats and
reduces the levels of the male-selective cytochromes P450,
including major enzymes like CYP2C11 and CYP3A2.
David Waxman's group (among others) characterised this nicely, e.g.
LeBlanc GA and Waxman DJ J.Biol.Chem. 263, 15732-15739 (1988)
I assume that carboplatin could have similar effects.
I hope that this helps.
All the very best,
Bernard
Bernard Murray, Ph.D.
Senior Research Scientist
Drug Metabolism, Gilead Sciences, Foster City, USA
bernard.murray.-a-.gilead.com
Back to the Top
Hi, Wang jian,
Please see the two following reference for in vitro induction study:
CYP3A4 induction by Xenobiotics: Biochemistry, experiemtnal methods,
and impact on drug discovery and development. Current drug
metabolism, 2004, 5, 483-505 (review).
CYP3A4 induction by drugs: correlation between a PXR reporter gene
assay and CYP3A4 expression in human hepatocytes Drug metabolsim and
Disposition, vol (30), 2002,795-
--
Hong(Lucy) Lu
Sr. Research Associate
Synta Pharmaceutical Corp.
Lexington, MA
Back to the Top
The following message was posted to: PharmPK
Hi Wang Jian,
I recommend you to look at
www.fda.cder.guidance/clin3.pdf: "Drug metabolism/drug
interaction studies in the drug development process:
Studies in vitro".
Also look at
www.fda.cder.guidance/2635fnl.pdf: "In vivo drug
metabolism/drug interaction studies - ...".
I believe the info you will get to be of help to you.
Regards,
D. Terziivanov
Dimiter Terziivanov, MD,PhD,DSc, Professor
Head, Clinic of Clinical Pharmacology and Pharmacokinetics,
Univ Hosp "St. I.Rilsky",
15 Acad. I. Geshov st, 1431 Sofia, Bulgaria
Tel:(+ 359 2)8510639;(+ 359 2)5812 828.
Fax:(+ 359 2)8519309. e-mal: terziiv.-a-.yahoo.com
Back to the Top
The following message was posted to: PharmPK
Hi,Murray:
I am very sorry for my poor English and I am afraid I may not
explain the dosing regimen clearly.Both carboplatin and taxol are the
reference drugs.And the drug we tested is another drug which
administrated for 7 days via P.O..So the result is not caused by
carboplatin but by the test drug.
Anyway,your information given to me is very useful because we
also have met another problem:In the vehicle group,the carboplatin we
administrated also had sex-related differences and the clearence of
male was quicker than female.I think it is because of the gender
differnces of GFR.But in the test group we administrated the test
drug for 7 days,the clearence of male rats for carboplatin was slowed
and tend to be equal to the female rats. I don't know it is
why.Because the elimination of carboplatin is only determined by
GFR.Who can tell me why?
Thanks a lot!
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)