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Fellow Members Interested in Metabolism
My understanding is Ketoconazole is a Non Specific inhibitor of
Cytochrome P-450 (according to the original papers published by Jansseen
Pharmaceutica). It is a non specific inhibitor with somewhat more affinity
towards, CYP-450 3A4. In recent times I started seeing several papers
probing the metabolic pathway of drug candidates stating because the
metabolism of Drug X is inhibited by ketoconazole so Drug X metabolism is
mediated by CYP-450 3A4. In my opinion this type of observations are
ACCEPTING A FALSE HYPOTHESIS (TYPE II ERROR ??).
If we want to test whether a particular drug is metabolized by 3A4 or not the
best way is to see the effect of induction by Dexamethasone and also
looking for Inhibition of metabolism by Gestodene or Norethindrone which
are known to be Very specific inhibitors for CYP-450 3A4.
Can someone throw some light on this aspect.
Prasad Tata, Ph.D.
Department of Pharmacokinetics
Otsuka America Pharmaceutical, Inc.
2440, Research Blvd.
Rockville, MD 20850
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> If we want to test whether a particular drug is metabolized by 3A4 or not the
> best way is to see the effect of induction by Dexamethasone and also
> looking for Inhibition of metabolism by Gestodene or Norethindrone which
> are known to be Very specific inhibitors for CYP-450 3A4.
>
> Can someone throw some light on this aspect.
>
> Prasad Tata, Ph.D.
> Department of Pharmacokinetics
> Otsuka America Pharmaceutical, Inc.
> 2440, Research Blvd.
> Rockville, MD 20850
Just wanted to add that Rifampicin is beleived to be a most potent
inducer of CYP3A4 subfamily mRNA. Other inducers include phenobarbitol
and Pregnenolone 16alpha-carbonitrile.
Both Ketoconazole and gestodene, albeit very potent, are a non-selective
inhibitor of CYP3A4. Troleandomycin is presumed to be a very specific
inhibitor of CYP3A4.
So, Rifampicin and Troleandomycin can be used to identify the cytochrome
P4503A4 isoform.
Additionally, the purified CYP3A4 (not easily available) can also be used.
FYI, I maintain a PK/PD/Biopharmaceutics Home Page that also has a table of
different P450 isoforms, some substrates, inducers and inhibitors. The URL
is given in my attached signature file.
Hope this helps.
G Krishna
--
Gopal Krishna, Ph.D. Candidate (Pharmacokinetics/Biopharmaceutics)
Maintainer: PK/PD/Biopharmaceutics Home Page-
http://griffin.vcu.edu/~gkrishna/PK/pk.html
Email: Gkrishna.aaa.Gems.VCU.EDU
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>Fellow Members Interested in Metabolism
>
>My understanding is Ketoconazole is a Non Specific inhibitor of
>Cytochrome P-450 (according to the original papers published by Jansseen
>Pharmaceutica). It is a non specific inhibitor with somewhat more affinity
>towards, CYP-450 3A4. In recent times I started seeing several papers
>probing the metabolic pathway of drug candidates stating because the
>metabolism of Drug X is inhibited by ketoconazole so Drug X metabolism is
>mediated by CYP-450 3A4. In my opinion this type of observations are
>ACCEPTING A FALSE HYPOTHESIS (TYPE II ERROR ??).
>
>If we want to test whether a particular drug is metabolized by 3A4 or not the
>best way is to see the effect of induction by Dexamethasone and also
>looking for Inhibition of metabolism by Gestodene or Norethindrone which
>are known to be Very specific inhibitors for CYP-450 3A4.
>
>Can someone throw some light on this aspect.
>
>Prasad Tata, Ph.D.
>Department of Pharmacokinetics
>Otsuka America Pharmaceutical, Inc.
>2440, Research Blvd.
>Rockville, MD 20850
>
Using induced microsomes to determine the primary cytochrome P450
responsible for metabolizing a substrate is questionable. Upon induction,
you can markedly change the relative composition of specific P450s in the
liver - some non-constitutive enzymes will beexpressed after induction,
while some constitutive P450s will be suppressed. Hence, using induced
microsomes may lead to an inaccurate conclusion as to the primary P450
responsible for metabolizing a substrate. We found this to be the case with
dapsone (see Vage C & Svensson CK. Drug Metab Dispos 22:572, 1994.). It is
also important to recognize that substrate concentration can influence which
P450 predominates in the metabolism of a substrate. Hence, the best way to
make this assessment is via a battery of experiments.
#################################
Craig K. Svensson, Pharm.D., Ph.D.
Department of Pharmaceutical Sciences
Wayne State University
Detroit, MI 48202 USA
Phone: (313) 577-0823
Fax: (313) 577-2033
E-mail: cks.at.wizard.pharm.wayne.edu
http://wizard.pharm.wayne.edu/svenss.html
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Dr. Swanson,
Your observation that it is better to test inhibition reactions in constituent
stage is a good time tested idea. However to quickly pin point what isoform
is responsible for the metabolism of Drug X many people used induction of
selective isoform and looking for corresponding increase in a particular
metabolite formation (metabolic pathway) and subsequent inhibition by a
selective inhibitor. This strategy provides quick way of getting a feel on the
major metabolic pathways based on these initial experiments further
experiments can be planned for further probing the metabolic profile of a
drug candidate.
My question is whether we can classify Ketoconazole as a Specific inhibitor
of CYP 3A4 or it is a non specific inhibitor of CYP-450.
Regards,
Prasad Tata
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