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Hi all,
This is the first time I am posting a mail on Pharm PK.
I have a few queries....
Can evalution of CYP induction studies be done in rats
Can anyone provide me with the basic protocol/references for carrying out CYP induction in
human hepatocytes and HepG2 cell lines
When can you say the compound is a potent inducer.
Thanks and kind regards
--
Alice Varghese
Assistant Professor
Pharm. Chem. Department
School of Pharmacy and Technology Management
NMIMS, Mumbai, India
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Dear Alice-
CYP induction studies are typically done in multiple species; and
normally at least in the species chosen for tox studies (e.g., to help
interpret tox study results).
Others can supply the most relevant references that you seek for human
hepatocytes, etc.
One way to identify a compound as a potent inducer is to include a known
inducer in each study as a comparator, and then, as defined in the study
protocol, anything found to be within a certain range relative to the
chosen comparator would be defined as either a high, moderate, or non
inducer. You should probably set the ranges in the protocol or some way
in advance, but regulatory reviewers may still have their own criteria,
based on the results that they see from all studies that they see.
-Tom
Thomas L. Tarnowski, Ph.D.
CACO Board / Organizing Committee
ttarnowski1.aaa.aol.com
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Dear Alice,
Please find the link below for Guidance for Industry (Drug Interaction
studies---Study design, Data analysis, and Implications for dosing and
labeling) Draft Guidance, September 2006 Clinical Pharmacology,
CDER/CBER.
Hopefully all your queries will be solve from the same.
http://www.abclabs.com/Portals/0/FDAGuidance_DraftDrugInteractionStudies2006.pdf
Best Regards,
Aslam Burhan,
Research Scientist,
Piramal Healthcare Ltd.,
Mumbai-63
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Hi Alice,
yes, it is possible to conduct induction studies on rat hepatocytes
fresh or cryopreserved.
As HepG2 does not express all CYPs, I prefer to work with the HepaRG
cell line, which can completely replace a batch of human hepatocytes
while all nuclear receptors are present and inducible.
The conventional procedure is as follows:
48 hoursof incubation to induce the activity and 24 hours for mRNA.
Reference inducers are:
omeprazole at 50 uM for CYP1A2, phenobarbital at 1 mM for CYP2B6 and
rifampicin at 10 uM for CYP3A4
Specific substrates are phenacetin for CYP1A2, bupropion for CYP2B6 and
nifedipine for CYP3A4
Francoise
Francoise BREE
Project Manager
XENOBLIS- CRO
France
francoise.bree.-at-.xenoblis.com
http://www.xenoblis.com
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Hi Alice
You may find the following papers and the references therein useful.
Almond LM, Yang J, Jamei M, Tucker GT and Rostami-Hodjegan A (2009)
Towards a Quantitative Framework for the Prediction of DDIs Arising from
Cytochrome P450 Induction. Curr Drug Metab 10:420-432.
Chu V, Einolf HJ, Evers R, Kumar GN, Moore D, Ripp SL, Silva J, Sinha V,
Sinz M and Skerjanec A (2009) In VITRO AND IN VIVO INDUCTION OF
CYTOCHROME P450: A SURVEY OF THE CURRENT PRACTICES AND RECOMMENDATIONS:
A PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA)
PERSPECTIVE. Drug Metab Dispos:dmd.109.027029.
Fahmi OA, Boldt S, Kish M, Obach RS and Tremaine L (2008) Prediction of
drug-drug interactions from in vitro induction data: application of the
relative induction score approach using cryopreserved human hepatocytes.
Drug Metab Dispos 36:1971-1974.
Yang J, Liao M, Shou M, Jamei M, Yeo KR, Tucker GT and Rostami-Hodjegan
A (2008) Cytochrome P450 turnover: regulation of synthesis and
degradation, methods for determining rates, and implications for the
prediction of drug interactions. Curr Drug Metab 9:384-394.
Regards
Masoud
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Hello Alice,
For to know when a drug is a potent, strong inductor/inhibition you can
revise tables in FDA page. Moreover, the draft of FDA about drug-drug
interactions could help you: "Drug interactions Studies- Study Design,
Data Analysis, Implications for Dosing, and Labeling Recommendations"
Regards
Teresa Nadal
Pharmacokinetic and Bioanalysis Project Manager
Noscira
Spain
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The following message was posted to: PharmPK
Dear Francoise,
I am very surprised of your mention about HepaRG, as in our lab we're affording the high
cost of purchasing human hepatocytes for potential CYP inducer screening. We once wondered
is it worth spending that much to obtain pre-clinical data of an NCE evaluation. We had
tried to use rat instead of human hepatocytes, but literatures show that CYP induction may
vary a lot from species to species. Is HepaRG commonly accepted for regular evaluations of
CYP induction in an in vitro model? If so, how many passages of the cell line can be used
and, can you kindly tell me the estimated cost? Also, does FDA accept the data of using
HepaRG in an IND submission?
Looking forward to your kind reply and thank you very much.
Sincerely,
Ralf
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Hi All,
There are more recent guidelines about DDI on town:
http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/05/WC500090112.pdf
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf
Aslam Burhan
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Guidelines are guidelines, my suggestion is to evaluate your compound
needs and design your experiments to understand extent, mechanism and
role of metabolism in the overall life cycle management of your drug.
Many times this requires going above and beyond what guidelines
stipulate.
Hope this helps,
Prasad NV Tata, Ph.D., FCP
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