1. Plasma stability

2. 12.1 Plasma Stability Fundamentals
Blood contains hydrolytic enzymes.
(cholinesterase, aldolase, lipase, dehydropeptidase, alkaline, acid phosphatase)
Compound decomposition can be catalyzed in plasma by hydrolytic enzymes.

3. 12.1 Plasma Stability Fundamentals
If the compound has affinity for these enzymes and it has a hydrolyzable group, it can be decomposed in the plasma.
- Ester
- Amide
- Carbamate
- Lactam
- Lactone
- Sulfonamide
- peptides and Peptide mimetics
Increased clearance

4. 12.1.1 Consequences of Chirality on Plasma Stability
Plasma stability is affected by chirality, owing to differential binding of enantiomers to plasma enzymes.

5. 12.2 Effect of Plasma Stability
In the blood, a hydrolytic enzyme cleaves the prodrug to release the active drug.
Antedrugs (soft- drugs)
- the opposite prodrugs
- active locally but rapidly degrade to an inactive compound once they reach the bloodstream
- To reduce side effects by minimizing the systemic toxicity of the drug

6. 12.2 Effect of Plasma Stability

8. 12.2 Effect of Plasma Stability
The plasma stability of compound increased order
: rat < dog < human

9. 12.3 Structure Modification Strategies to improve Plasma Stability

10. 12.3.1 Substitute an amide for an Ester
Amides are more stable against plasma hydrolysis.

11. 12.3.2 Increase Steric Hindrance
Addition of steric hindrance near a hydrolyzable group can increase plasma stability.

12. 12.3.2 Increase Steric Hindrance
Addition of steric hindrance near a hydrolyzable group can increase plasma stability.

13. 12.3.3 Electron-withdrawing Groups Decrease Plasma Stability for Antedrug
Including EWG increased the positive charge on the phosphorous atom and increased the rate of hydrolysis

14. 12.4 Applications of Plasma stability Data
① Diagnose Poor In Vivo Performance
② Alert Teams to a Liability
③ Prioritize Compounds for In Vivo Animal studies

15. 12.4 Applications of Plasma stability Data
④ Prioritize Synthetic Efforts

16. 12.4 Applications of Plasma stability Data
⑤ Screening of Prodrugs

17. 12.4 Applications of Plasma stability Data
⑥ Guide Structural Modification

18. Problems
1. Which of the following structures might be partially or completely unstable in plasma?

19. Problems
2. List two applications where plasma instability is advantageous. - Prodrugs, Antedrugs

20. Problems
3. What are some structural modifications that you could try in order to improve the plasma stability of the following compound?

21. Problems
4. Microsomes have hydrolysis activity. Are they useful for assessing potential plasma hydrolysis? - No. The hydrolysis enzymes in microsomes and plasma are different and should be assessed separately. 5. Which of the following groups should alert you to potential degradation due to plasma hydrolysis? : (a) phenyl, (b) carboxylic acid, (c) ester, (d) lactone, (e) trifluoromethyl, (f) carbamate, (g) amide