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Cytochrome P450 Inhibition
2015-12-23 손한표
Overview
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Drug-drug interactions can occur when two drugs are coadministered and compete for the same enzyme.
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In cytochrome P450(CYP) inhibition, one drug(“perpetrator”)
binds to the isozyme and the other drug(“victim”) is excluded
from metabolism, thus increasing to a toxic concentration
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Irreversible binding inactivates CYP and is termed mechanismbased inhibition
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CYP inhibition can cause withdrawal from clinical use or
restrictive labeling for a drug
Introduction
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Many patients receive more than one drug at a time;
physicians must be careful to avoid drug-drug interaction.
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A major DDI concern is cytochrome P450 (CYP)
inhibition.
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CYP inhibition effects on clearance and half-time.
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CYP inhibition now is asseced for a lead series from the
ealiest stages of the discovery project.
CYP Inhibition Fundamentals
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Cytochromes P450
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One seires of oxidase enzymes.
The active site of CYP contains a heme-iron center.
The iron is tethered to the protein via a cystein thiolate ligand.
The term P450 is derived from the spectrophotometric peak
at the wavelength of the absorption maximum of the enzyme
(450 nm) when it is in the reduced state and complexed with
CO.
CYP Inhibition Fundamentals
CYP3A4
CYP2D6
CYP Inhibition Fundamentals
CYP Inhibition Fundamentals
CYP Inhibition Fundamentals
Effects of CYP Inhibition
Terfeneadine
Erythromycin
Effects of CYP Inhibition
-During initial in vitro CYP inhibition assessment, often at a test compound of 3 𝜇M, the
following guidelines.
Effects of CYP Inhibition
Effects of CYP Inhibition
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CYP3A4 vs CYP2C19
Plasma protein binding
Cmax & Ki
CYP Inhibition Case Studies
CYP Inhibition Case Studies
CYP Inhibition Case Studies
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Consequences of Chirality on CYP Inhibition
(+)-isomer :
CYP2C9 more
inhibition!
Quinidine :
CYP2D6 Inhibition
Quinine : NOT
inhibtion
Structure Modification Strategies to Reduce
CYP Inhibition
Structure Modification Strategies to Reduce
CYP Inhibition
Structure Modification Strategies to Reduce
CYP Inhibition
Structure Modification Strategies to Reduce
CYP Inhibition
Reversible and Irreversible CYP Inhibition
Inhibition
Reversible
Irreversible mechanism-dependant
Formation
covalent bond
Tight
quasiirreversible
binding
Reversible and Irreversible CYP Inhibition
Problems
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1.For initial CYP inhibition screening, a useful goal is an
IC50 greater than what concentration?
10𝜇M
2.For human studies, Ki should be what? At what
concentration is there likely to be CYP inhibition?
greater than 10times than Cmax. When concentration
greater than Ki
3.Why was Saldane removed from the market?
because its metabolism at CYP3A4 was inhibited by
3A4 inhibitor. Such as erythromycin.
Problems
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4.what is difference between reversible and mechanismbased CYP inhibition? How can you distinguish these
mechanism?
Reversible : inhibitor binds and releases from the
enzyme.
Irreversible : inhibitor binds to enzyme by covalent
interaction or strong complexation interatction.
Time dependacy of inhibition.
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5. How might you modify the following structure to
reduce CYP inhibition?

Problems
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6.What is the risk associated with CYP inhibition?
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A. a coadministered drug is metabolized too quickly,
B. a compound is not stable,
C. a coadministered drug is not metabolized quickly enough,
D. an isozyme may be induced.
7. Should CYP inhibition be used to estimate metabolic
stability?
NO