1. Cytochrome P450 Inhibition
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2. Overview
Drug-drug interactions can occur when two drugs are co- administered and compete for the same enzyme.
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
Irreversible binding inactivates CYP and is termed mechanism- based inhibition
CYP inhibition can cause withdrawal from clinical use or restrictive labeling for a drug

3. Introduction
Many patients receive more than one drug at a time; physicians must be careful to avoid drug-drug interaction.
A major DDI concern is cytochrome P450 (CYP) inhibition.
CYP inhibition effects on clearance and half-time.
CYP inhibition now is asseced for a lead series from the ealiest stages of the discovery project.

4. CYP Inhibition Fundamentals
Cytochromes P450
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.

5. CYP Inhibition Fundamentals
CYP2D6
CYP3A4

6. CYP Inhibition Fundamentals

7. CYP Inhibition Fundamentals

8. CYP Inhibition Fundamentals

9. Effects of CYP Inhibition
Terfeneadine
Erythromycin

10. Effects of CYP Inhibition
-During initial in vitro CYP inhibition assessment, often at a test compound of 3 𝜇M, the following guidelines.

11. Effects of CYP Inhibition

12. Effects of CYP Inhibition
CYP3A4 vs CYP2C19
Plasma protein binding
Cmax & Ki

13. CYP Inhibition Case Studies

14. CYP Inhibition Case Studies

15. CYP Inhibition Case Studies
Consequences of Chirality on CYP Inhibition
Quinidine : CYP2D6 Inhibition
Quinine : NOT inhibtion
(+)-isomer : CYP2C9 more inhibition!

16. Structure Modification Strategies to Reduce CYP Inhibition

17. Structure Modification Strategies to Reduce CYP Inhibition

18. Structure Modification Strategies to Reduce CYP Inhibition

19. Structure Modification Strategies to Reduce CYP Inhibition

20. Reversible and Irreversible CYP Inhibition
Formation covalent bond
Tight quasiirreversible binding
mechanism-dependant

21. Reversible and Irreversible CYP Inhibition

22. Problems
1.For initial CYP inhibition screening, a useful goal is an IC50 greater than what concentration?
2.For human studies, Ki should be what? At what concentration is there likely to be CYP inhibition?
3.Why was Saldane removed from the market?
10𝜇M
greater than 10times than Cmax. When concentration greater than Ki
because its metabolism at CYP3A4 was inhibited by 3A4 inhibitor. Such as erythromycin.

23. Problems
4.what is difference between reversible and mechanism- based CYP inhibition? How can you distinguish these mechanism?
5. How might you modify the following structure to reduce CYP inhibition? 
Reversible : inhibitor binds and releases from the enzyme. Irreversible : inhibitor binds to enzyme by covalent interaction or strong complexation interatction. Time dependacy of inhibition.

24. Problems 6.What is the risk associated with CYP inhibition?
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