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Dear All
Could anyone help explain the following:
* We were trying to identify DDI amongst two drugs using HLM.
On co incubation we saw increase in one of the metabolites which is
reproducible in 3 different experiments.
* However, we do not see such increase when we increased the
concentrations of both the drugs, again, reproducible.
Can anybody help explain these results.
Geeta
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Dear Geeta,
if you are talking about co incubation in the second case as well, I
would think about toxicity (How much was the "increased"
concentration?).
Hope this help.
Monica Rigo
Bioanalytics, Metabolism and in vitro Technologies
GlaxoSmithKline
Via Fleming 4, 37135 Verona- ITALY
Psychiatric CEDD DMPK Verona ITALY
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Dear Geeta Sharma
The case you had mentioned could have the following reasons
1. As you are working with DDI studies, in the coincubation one drug
might inhibit the metabolism of the other.
2. Well you had mentioned increase in the concentration of both, but
you were not clear whether you are increasing the conentration of one
of the drug at a time or not.
Any way, the reason could be either one of the drug is inhibiting the
metabolism of another so you are not able to observe the metabolite
or the drug itself may act as inhibitor of its own metabolism.
Regards
Chris
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Dear Chris,
Do you an example a drug that inhibits its own metabolism?
Thank you in advance.
Regards
Raju
[Any drug that undergoes saturable metabolism? - db]
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The following message was posted to: PharmPK
Conivaptan
Diltiazem metabolites inhibit diltiazem metabolism
Verapamil
Susan Shoaf
Otsuka Pharmaceutical Development and Commercialization, Inc.
Rockville MD
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Dear raju
Kindly look in to the article
Drug Metab. Dispos. 2001 29: 368-374.
Chris
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The following message was posted to: PharmPK
Dear Nagaraju,
A drug that may "inhibit its own metabolism", this is not so clear to
me.
One can be tempted to apply this definition to examples like mibefradil,
which first appeared as metabolically stable, and was in turn shown to
be is a strong inhibitor of most major human CYPs, probably through
reversible and irreversible mechanisms.
However, only careful kinetic study may help demonstrate that one
substrate is also an inhibitor of the reaction (since in that particular
case, you cannot run the control "without inhibitor" condition to assess
the 100% velocity level, of course...).
Your definition may apply to:
- the "normal" Michaelis-Menten kinetics, as suggested by David: the
metabolism of any drug undergoes saturation at high substrate
concentration; this is the normal substrate inhibition, I believe
- the drugs of which metabolites do produce inhibition: this is product
inhibition (in my view, the product keeps some affinity for the active
site and competes with the substrate for access to the enzyme).
- any mechanism-based inhibitor (many macrolides, for instance) can be
considered as inhibiting its own metabolism, since it is metabolized
into an enzyme-inactivating species (this is roughly the irreversible
case of product inhibition).
I remember that a number of J. Brain Houston's nice papers deal with
usual and unusual metabolism kinetics, encompassing substrate- and
product-inhibition as well as enzyme activation.
Best regards,
Frederic Massiere, Oroxcell.
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