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The following message was posted to: PharmPK
I will appreciate if members can provide me with explanation/
information on mechanism based inhibition of enzymes. Any references
will be very useful.
Thanks
Ananda
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The following message was posted to: PharmPK
Ananda,
In the case of mechanism-based inhibition, the inhibitor is
metabolically activated by an enzyme and irreversibly inactivates the
same enzyme by covalent binding, exhibiting the following
characteristics:
1. Preincubation time-dependent inhibition of the enzyme (time
dependence).
2. No inhibition if the cofactors necessary to produce the activated
inhibitor (e.g., NADPH for P450 metabolism) are not present in the
preincubation medium.
3. Potentiation of the inhibition depending on the inhibitor
concentration (saturation kinetics).
4. Slower inactivation rate of the enzyme in the presence of
substrate compared with its absence (substrate protection).
5. Enzyme activity not recovered after gel filtration or dialysis
(irreversibility).
6. 1 : 1 Stoichiometry of the inhibitor and the active site of the
enzyme (stoichiometry of inactivation).
I hope this is helpful.
Regards,
Anila
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Hi Ananda,
For all the basic concepts about MBI, you may have a look on these
golden references :
- Enzyme Kinetics by I.H. Segel, 1975, John Wiley & Sons, New York
- Mechanism-Based Enzyme Inactivation: Chemistry and Enzymology, Vols I
and II, by R.B. Silverman, 1988, CRC Press, Boca Raton, FL (USA)
For MBI of metabolic enzymes and the risk of drug-drug interaction, a
few issues are worth noting:
- The enzyme inhibition effect remains after the inhibiting species
(drug, for example) is cleared from the body. Since the enzyme is
inactivated, the activity may get back to normal level only when the
protein is re-synthesised.
- Because of the time-dependency of the phenomenon, dramatic inhibition
may not be detected in in-vitro tests, unless specific test design.
- Despite potential dramatic DDI, a number of drugs on the market are
mechanism-based inhibitors of metabolic enzymes (some antibiotics, for
instance).
Frederic MASSIERE, Oroxcell
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The following message was posted to: PharmPK
Mechanism based inhibition of Cytochrome P450 3A4 by Therapeutic
drugs: Clin
Pharmacokinet 2005; 44(3) : 279-304 may be a useful reference.
Regards,
Martin
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