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Dear all,
I am trying to model drug interaction study data to estimate enzyme
turn over parameters. The inhibitor used is a mechanism based
inhibitor. I am trying to find an equation to describe Time
dependent changes in clearance due to inhibitor administration.
However, I could not find any for inhibition but found for
induction. Can anyone suggest me or quote reference for me in this
regard?
I appreciate your assistance.
-Ayyappa Chaturvedula
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The following message was posted to: PharmPK
Hi,
Changes in clearance due to inhibitor are perhaps better defined as
inhibitor dependent rather than time dependent. But of course I
expect the inhibitor conc changes with time so that the clearance
appears to change with time.
To model this kind of process you need to express the PK in the form
of differential equations e.g. like this without inhibitor
dC/dt = (Ratein - CL*C)/V ; without inhibitor
and like this with a PK model for the inhibitor
dCI/dt = (RateinI - CLI*CI)/VI ; inhibitor PK model
dC/dt = (Ratein - CL*(1-CI/(KI+CI))*C)/V ; with inhibitor
CI is the conc of inhibitor implemented as a differential equation to
describe the time course of inhibitor conc.
The equation for the conc (C) of drug whose clearance is inhibited is
also expressed as a differential equation. It is now modified with an
inhibitory Emax type model which assumes that the inhibitor can
completely inhibit the drug clearance. 50% of this inhibition occurs
when the inhibitor conc, CI, is equal to KI.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Hi Nick, Hi Chaturvedula,
I believe that the situation with a mechanism-based inhibitor is
quite different from that with a reversible inhibitor. In the latter
well-known case, the drug-metabolizing enzyme is affected by the
presence of the inhibitor, and clearance immediately returns to
normal level when the inhibitor is cleared away. Changes in clearance
highly depend on the concentration of the inhibitor and its affinity
for the enzyme (measured by the inhibition constant Ki).
In the case of MBI, the enzyme is irreversibly destroyed
(inactivated) by the action of the inhibitor and does not recover
after the inhibitor is gone. Therefore:
- regarding the onset, we have to consider the kinetics of
inactivation which is quite different from the case of reversible
inhibition: determination of a constant of irreversible inhibition K
(irr) and a rate constant k(inact). - on the other hand, once the
enzyme is inactivated (totally or partially), the global situation
is similar to that of a poor metabolizer, or to any situation with
impaired enzyme expression. Although the situation is temporary,
kinetics of the return to normal metabolic activity are much similar
to enzyme induction.
Chaturveda, I'm sorry I have not specifically monitored that topic,
but I believe that interesting advances have been made by others on
the subject of prediction of DDI in case of MBI (driven by the
concern about CYP3A4 inhibition by mibefradil, mefepristone, and
other drugs). As a starting point, you could have a look on:
- Mayhew BS at al, Drug Metab Dispos 2000, 28:1031-1037 (an in vitro
model for predicting in vivo inactivation of CYP3A4)
Hope that helps.
Best regards,
Frederic MASSIERE, Oroxcell
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The following message was posted to: PharmPK
Hi,
Here is one of the latest references that you may find helpful:
Akiko Watanabe, Koichi Nakamura, Noriko Okudaira, Osamu Okazaki, and
Ken-ichi Sudo, Risk Assessment for Drug-Drug Interaction Caused by
Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay
Systems and Its Application in the Early Drug Discovery Process, Drug
Metab Dispos 2007 35: 1232-1238.
Thanks,
Kishore
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Dear Ayyappa
As explained by Frederic the kinetics of mechanism (time)-based
inhibition is more complex than competitive inhibition, for the full
story please look at:
Silverman R.B., 1988. Mechanism-Based Enzyme Inactivation: Chemistry
and Enzymology. CRC Press, Boca Raton.
Also, you may find the following paper useful:
Yang J, Jamei M, Yeo KR, Tucker GT and Rostami-Hodjegan A (2007)
Theoretical assessment of a new experimental protocol for determining
kinetic values describing mechanism (time)-based enzyme inhibition.
Eur J Pharm Sci 31:232-241.
However, for estimating enzyme turn over parameters you need to
simplify this process (adding some assumptions) as the process is
very complex and you need lots of data points to determine the
parameters confidently. In the following paper the turn over numbers
from different sources and for different enzymes are collected which
gives you good starting estimates:
Ghanbari F., Rowland-Yeo K., Bloomer J.C., Clarke S.E., Lennard M.S.,
Tucker G.T., Rostami-Hodjegan A., 2006. A critical evaluation of the
experimental design of studies of mechanism based enzyme inhibition,
with implications for in vitro-in vivo extrapolation. Curr. Drug
Metab. 7, 315-334.
Hope this helps.
Masoud
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Dear Nick and Frederic,
Thank you for your responses. Doesn't the model sent by Nick
describe in both conditions? I agree that the recovery is quiet
different in both the modes, however the onset may be mathematically
similar. Interpretation of KI should be left to the modeler based on
the mechanism of inhibition.
Thanks
Ayyappa Chaturvedula
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