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Dear all,
I am wondering what kind of effect I would expect from a competitive
inhibitor vs a mechanism-based inhibitor with respect to various in
vivo PK parameters such as Cmax, t1/2, Tmax, etc. of the substrate.
Does it depend on both the inhibitor as well as substrate
concentration? I can't seem to find any resources on the internet that
describes this.
Thanks in advance,
Eric
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The following message was posted to: PharmPK
Dear Eric
As you can imagine the in vivo effects of drug-drug interaction (DDI)
can
significantly vary based on the mechanism of interaction. Also, there
are
many factors that influence in vivo consequences of DDI, for example the
substrate and inhibitor(s) doses, their rate and extent of absorption
including their formulations, the enzymes metabolising each moieties and
their contributions (fm), first pass vs systemic interactions, non-
metabolic
routes of elimination, potency of inhibitors, enzymes turnover in the
liver
and gut and on top of all these you need to add inter-individual
variability
which can hugely affects the outcome.
There are some cases where the inhibitor metabolites also interact with
other moieties such as the OH-itraconazole
http://dx.doi.org/10.1038/sj.clpt.6100230
or N-desmethyl-diltiazem which
is also a mechanism-based inhibitor
http://dx.doi.org/10.1124/dmd.106.013847
Evidently, the ideal approach to
incorporate all these factors is the use of physiologically-based
pharmacokinetics models.
You may find the following papers useful:
http://dx.doi.org/10.2174/138920007780866861
http://dx.doi.org/10.1080/00498250701670945
http://dx.doi.org/10.1124/dmd.105.003715
http://dx.doi.org/10.1023/A:1007509324428
For your added information we thoroughly discuss and investigate these
effects during our hands-on IVIVE workshops, please see:
http://www.simcyp.com/ProductServices/Workshops/.
Best Regards
Masoud
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The following message was posted to: PharmPK
Eric,
> I am wondering what kind of effect I would expect from a competitive
> inhibitor vs a mechanism-based inhibitor with respect to various in
> vivo PK parameters such as Cmax, t1/2, Tmax, etc. of the substrate.
> Does it depend on both the inhibitor as well as substrate
concentration?
If you believe in mechanism based inhibition in vitro then why would you
not think the same kind of mechanism does not work in vivo? I would
certainly expect the reaction to depend on substrate as well as
inhibitor concentration. Of course, its typically much harder to know
substrate conc and the inhibitor conc is typically only known in plasma
but you can start from there.
Be aware the your inhibitor will affect drug clearance. Any effects on
PK statistics you mention such as Cmax, Tmax, and T1/2 will be
secondary and complex
functions of the inhibitor mechanism. I would suggest using a PK model
and not rely on 'simple' analysis methods that typically are hard to
interpret without the rigour of an integrated PK model.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.-a-.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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Eric,
I would expect an increase in Cmax,AUC, t1/2 of the substrate when it
is given with inhibitor that are competitive or mechanism based. The
main difference I would see between those two will be the recovery
after cessation of inihibitor. In case of mechanism based inhibition,
the recovery of substrate half-life will be longer because the enzyme
should be reproduced. In case of competitive inhibitor the recovery
will be instantaneous after the cessation of inhibitor treatment.
Ayyappa Chaturvedula
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