1. Phase-I Drug Metabolism Pharmaceutical Medicinal Chemistry-I
Dr. Bilal Al-Jaidi
Assistant Professor in Medicinal Chemistry and Drug Design
Faculty of Pharmacy, Philadelphia University-Jordan

2. Learning Outcomes At the end of this lesson, students will be able to:
Define what Drug Metabolism mean.
Demonstrate the different routes of Phase-I metabolism in body.
Explain the effect of Drug Metabolism on drug ‘s duration of action and activity.
Classify mechanism of drug metabolism-Phase-I.
Outline the role of drug metabolism in drug toxicity and carcinogenicity.

3. Drug metabolism
Refers to enzyme-mediated biotransformations (detoxication) that alter the pharmacological activity of both endogenous and exogenous compounds.

4. Drug metabolism
Drugs undergo a variety of chemical changes in the animal organism by enzymes of the liver, intestine, kidney, lung, plasma and other tissues.
Many enzymes take place in such biotransformations; oxidase, hydrolase, lipase, synthetase, dehydrogenase, …etc

5. Blood
CNS
Muscles
Heart

6. Metabolism may result in:
Pharmacologically inactive drug (detoxification).
Pharmacologically active drug (bioactivation…prodrug approach).
Change the pharmacological activity (toxic effect).

7. The importance of studying drug metabolism:
Understanding the pharmacological and toxicological activity of drugs.
The importance of shortening the drug’s duration of action.
The complications of drug-drug interactions mainly depends on the induction or inhibition of metabolic enzymes

8. Drug metabolism Can be divided into two distinct categories: Phase-I:
Reactions which introduce or unmask hydrophilic groups in the drug structure (functionalisations).
Phase-II:
Reactions which conjugate the drug or its phase-I metabolite with a hydrophilic, endogenous species (conjugation reactions).

9. Phase-I reactions Aliphatic hydroxylation. Oxidation: Reduction.
Oxidative Dealkylation.
Oxidative deamination.
N and S oxidation.
Alcohol/aldehyde dehydrogenase.
Reduction.
Hydrolysis.

10. Phase-II metabolism
Involves the following conjugation reactions that are catalyzed by transferase enzymes:
Glucuronidation.
Sulfation.
Amino acid conjugation.
Methylation.
Acetylation.

11. Phase-I reactions
Two general types of enzyme systems take part in these reactions:
Microsomal Mixed Function Oxidases (MFOs)
Flavoprotein, NADPH-monooxygenase
Cytochrome P450
Non-cytochrome oxidizing enzymes.
Xanthine oxidase
Alcohol/aldehyde dehydrogenase

12. General features of Cytochrome P-450
A large number of families (at least 18 in mammals) of cytochrome P-450 (abbreviated “CYP”) enzymes exists as well as many subfamilies.
each member catalyzes the biotransformation of a unique group of drugs
some overlap in the substrate specificities.

13. Families and subfamilies
CYP 450
Families and subfamilies
Foye's principles of medicinal chemistry

14. CYP Biotransformations
Chemically diverse small molecules are converted, generally to more polar compounds
Reactions include:
Aliphatic hydroxylation, aromatic hydroxylation
Dealkylation (N-,O-, S-)
N-oxidation, S-oxidation
Deamination
Dehalogenation

15. Oxidative Phase-I involving cytochrome P-450 enzymes:
Aliphatic hydroxylation:
Mainly occur on the ultimate (ω) or penultimate (ω-1) carbon atom in the structure.
Also it occurs at an activated carbon atom, that is next to sp , sp2 carbons:

16. Oxidative Phase-I involving cytochrome P-450 enzymes:
Aliphatic hydroxylation:
Mainly occur on the ultimate (ω) or penultimate (ω-1) carbon atom in the structure.
Also it occurs at an activated carbon atom, that is next to sp , sp2 carbons:

17. Oxidative Phase-I involving cytochrome P-450 enzymes:
Aromatic hydroxylation:

18. Aromatic epoxidation:
DNA

19. Oxidative Phase-I involving cytochrome P-450 enzymes:
Alkene epoxidation:

20. Glutathione conjugation
For electrophilic drugs and metabolites:

21. Detoxication by glutathione adduct formation

22. Glutathione conjugation
Toxicity of aromatic compounds came from the formation of arene oxide during the metabolism that will be attacked by endogenous nucleophile such as proteins, DNA or RNA.

23. Glutathione conjugation

24. O-dealkylation:

25. N-dealkylation:

26. N-dealkylation

27. Oxidative Phase-I involving cytochrome P-450 enzymes:
Oxidative deamination:

28. Oxidative Phase-I involving cytochrome P-450 enzymes:
N-oxidation:
Mostly for primary and secondary amines as well as aromatic amines:
This gives N-oxide that will be rapidly converted to hydroxylamines.

31. Hydrolytic phase-I metabolism
By non-specific esterase and amidase enzymes that present in plasma, gut, liver and kidney.
It has a beneficial role in most of prodrugs that after hydrolysis inside the body release the active form of the drug.

32. Ester vs. Amide bond
Ester bond is relatively weaker than amide bond, it will be rapidly hydrolyzed by esterase enzyme

33. Nucleophilic attack of hydroxide anion on ester and amide

34. Example Procaine Short acting local anesthetic Procainamide
Long acting antiarrhythmic
T1/2 = second
T1/2 = hr

35. Hydrolytic phase-I metabolism
Examples of prodrugs activated by hydrolytic enzymes:
Dipivefrine: is a di-tertbutylcarboxy ester of adrenaline…. More lipophilic… better penetration through the corneal membrane….then will be hydrolyzed to give the active form (adrenaline)

36. Why Dipifevrine has been prepared?
Adrenaline is a polar drug….difficult access into the ocular cavity.
Adrenaline has a generalized adrenergic effect…. Many side effects such as increase blood pressure, heart rate and bronchodilation.
Dipifevrine is more lipophilic, better penetration… localized effect.

37. Other phase-I metabolic enzymes
Alcohol dehydrogenase and aldehyde dehydrogenase:

38. Other phase-I metabolism
Heterocyclic ring oxidation:
S-dealkylation:

39. Other phase-I metabolism
Sulfoxidation: by flavin monooxygenase

40. Other phase-I metabolism
Azoreduction:
Antibacterial action
Anti-inflammatory action

41. General notes regarding phase-I metabolism
Hydrolysis normally catalyzed by carboxylesterases:
Cholinesterase…. Hydrolyzes choline-like esters (such as succinylcholine), procaine and acetylsalicylic acid.
Arylcarboxyesterase.
Liver carboxyesterase

42. Zwitter ionic
Polar
Easily excreted

43. General notes regarding phase-I metabolism
Esters that are sterically hindered are hydrolyzed more slowly and may be appeared unchanged in urine:

45. General notes regarding phase-I metabolism
Amides are more stable to hydrolysis than esters….large fraction of amide containing drugs are normally excreted unchanged.

46. Procaine has a short duration
of anesthesia
lidocaine has a long duration
of anesthesia

47. Nucleophilic attack of HO-

48. Aromatic hydroxylation
The least substituted aromatic ring will be favorably oxidized, especially at the least hindered carbon atom
The activated ring will be better oxidized (the ring bearing an electron donating group)

49. The least substituted aromatic ring will be favorably oxidized, especially at the least hindered carbon atom

50. The activated ring will be better oxidized (the ring bearing an electron donating group)
No aromatic hydroxylation

51. An introduction to Medicinal Chemistry by Graham L. Patrick
An introduction to Medicinal Chemistry by Graham L. Patrick. 4th edition, Oxford, 2009
Wilson and Gisvolds text book of organic medicinal and pharmaceutical chemistry by John H. Black and John M. Beale, jr. 12th edition, Lippincott Williams and Wilkings 2011.
Foyes principle of medicinal chemistry by David H. Williams, Thomas L. Leuke, Williams O. Foye. Lippincott William and Wilkins. 7th edition, 2013.

52. The End