1. METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS
Chapter 2
Roselyn Aperocho-Naranjo
USPF-College of Pharmacy

2. METABOLISM
> chemical reaction that occur in the body to maintain life
> allow organisms to grow and reproduce, maintain their structures, and respond to their environments
> divided into two categories:
* Catabolism breaks down organic matter
*Anabolism uses energy to build up or construct
components of cells such as proteins and
nucleic acids.

3. Background Drug molecules easily diffuse through membranes
Most drugs that enter the body are lipid-soluble
Metabolized in the liver
Reach the target site & produce a pharmacologic response

4. Background Of Drugs or Xenobiotics
Metabolism plays a central role in the
Elimination

5. Sites of Drug Biotransformation
2. Liver (hepatic metabolism
or First Pass Effect
The most important organ in
drug metabolism
Some drugs may decrease
Oral bioavailability
Lidocaine (ineffective)
Isoproterenol
Meperidine
Morphine
Nitroglycerin
Pentazocaine
Propoxyphene
Propranolol
salicylamide
1. Gastrointestinal Tract
Absorb orally administered drugs
3. Blood Circulation
Absorb orally administered drugs

6. General Pathways of Drug Metabolism
> Phase I or Functionalization
Reactions includes:
* Oxidative Reaction
* Reductive Reaction
* Hydrolytic Biotransformation

7. General Pathways of Drug Metabolism
Phase II or Conjugation Reaction
* Glucoronic Acid Conjugation
* Sulfate Conjugation
* Conjugation with Glycine, Glutamine and
other Amino Acids
* Glutathione or Mercapturic Acid Conjugation
* Acetylation
* Methylation

8. General Summary of Phase I and Phase II Metabolic Pathways
PHASE I or FUNCTIONALIZATION REACTIONS
B. Reductive Reactions
-Oxidation of Aromatic Moieties Reduction of aldehydes and ketones
Oxidation of Olefins Reduction of Nitro and Azo compounds
Oxidation of Benzyclic, Allylic carbon atoms, carbon Miscellaneous Reductive reactions
atoms ∂ Carbon atoms to carbonyl and imines
Oxidation of Aliphatic and Alicyclic carbon atoms C. Hydrolytic Reactions
Oxidation of Carbon-heteroatom systems: Hydrolysis of Esters and Amides
* Caron-Nitrogen system Hydration of Epoxides and arene oxide by
* Carbon – Sulfur system epoxide hydrase
* Caron – Oxygen system
Carbon – Alcohols and Aldehydes
Other miscellaneous oxidative reactions
PHASE II or CONJUGSTION REACTIONS
A. Glucuronic Acid Conjugation
B. Sulfate Conjugation
C. Conjugation with Glycine, Glutamine and other Amino Acids
D. Glutathione or Mercapturic Acid Conjugation
E. Acetylation
D. Methylation
A. Oxidation Reactions

9. General Summary of Phase I and Phase II Metabolic Pathways
PHASE I or FUNCTIONALIZATION REACTIONS
B. Reductive Reactions
-Oxidation of Aromatic Moieties Reduction of aldehydes and ketones
Oxidation of Olefins Reduction of Nitro and Azo compounds
Oxidation of Benzyclic, Allylic carbon atoms, carbon Miscellaneous Reductive reactions
atoms ∂ Carbon atoms to carbonyl and imines
Oxidation of Aliphatic and Alicyclic carbon atoms C. Hydrolytic Reactions
Oxidation of Carbon-heteroatom systems: Hydrolysis of Esters and Amides
* Caron-Nitrogen system Hydration of Epoxides and arene oxide by
* Carbon – Sulfur system epoxide hydrase
* Caron – Oxygen system
Carbon – Alcohols and Aldehydes
Other miscellaneous oxidative reactions
PHASE II or CONJUGSTION REACTIONS
A. Glucuronic Acid Conjugation
B. Sulfate Conjugation
C. Conjugation with Glycine, Glutamine and other Amino Acids
D. Glutathione or Mercapturic Acid Conjugation
E. Acetylation
D. Methylation
A. Oxidation Reactions

10. OXIDATIVE REACTIONS Oxidation of Aromatic moieties
-refers to the mixed-function oxidation of aromatic compounds (arenes) to their corresponding phenolic metabolites (arenols). R I R I R I O OH
Arene
Arene oxide
Arenol

11. Arene Oxides R I R I R I H I OH I O O H Arene oxide Arenols
A. Spontaneous arrangement R I R I R I H I OH I O O H
Arene oxide
Arenols

12. Example of Oxidation Reaction
Allylic Hydroxylation of Marijuana
(Δ1 tetra Hydrocannabinol)
CH3
CH2OH
CH3
CH3
CH3
CH3

13. Example of Oxidation Reaction
Allylic Hydroxylation of Marijuana
(Δ1 tetra Hydrocannabinol)
(CH3) H
H-C-OH H
H-C-H I
(CH2OH)

14. Example of Oxidation Reaction
1. Allylic Hydroxylation of Marijuana
(Δ1 tetra Hydrocannabinol)
CH3
CH2OH
CH3
7- Hydroxy Δ1 tetra Hydrocannabinol
CH3
CH3

15. Example of Oxidation Reaction
2. Oxidation of THC to Carboxylic Acid derivative
CH2OH
COOH
CH3
CH3
CH3
CH3
7- Δ1 tetra Hydrocannabinoic Acid
7- Hydroxy Δ1 tetra Hydrocannabinol

16. Example of Oxidation Reaction
3. Oxidation of THC to Carboxylic Acid derivative and Conjugation
with Glucuronic Acid
R – alkyl group
COOR O ll
C-O-
CH3
CH3
Glucuronide conjugate

17. Oxidation Reaction CH2OH –------ CHO ------------- COOH
Oxidation of Benzyclic Carbon Atoms
- the primary alcohol are often oxidized to form aldehydes and carboxyllic acids
CH2OH – CHO COOH
CH2OH
CH3
7- Hydroxy Δ1 tetra Hydrocannabinol
CH3
CHO
CH3
COOH

18. Oxidation Reaction
Oxidation of C atoms ∂ to Carbonyl’s & Imines
- is a mixed function oxidase system which involve C atoms adjacent to carbonyl and imino (C=N) group.
N-demethylation OH H OH H H
diazepam
3-hydroxydiazepam
oxazepam

19. Oxidation Reaction Oxidation at aliphatic and alicyclic C atoms
- aliphatic hydroxylation commonly take place in drug molecules with straight or branched alkyl chains.
Drugs that undergo Aliphatic Oxidation are the following:
Valproic Acid (Depakene) – antiepileptic agent
Barbiturates (Phenobarbital and Secorbarbital)
Oral hypoglycemic (Diabenese)
Sulfonylurea
Anti-inflammatory agent (Motrin)
Meprobamate
Glutethimide
Ethosuximide
Phenylbutazone

20. Important Therapeutic Agents that undergo Aromatic Hydroxylation
Propranolol Phenobarbital
back

21. Important Therapeutic Agents that undergo Aromatic Hydroxylation
Phenytoin Phenylbutazone

22. Important Therapeutic Agents that undergo Aromatic Hydroxylation
Ethinylestradiol Warfarin

23. Important Therapeutic Agents that undergo Aromatic Hydroxylation
Amphetamine

24. Important Therapeutic Agents that undergo Aromatic Hydroxylation
Deactivating groups generally slow or resist aromatic hydroxylation includes:
Chloro (Cl)
Amino group(NR3)
COOH
SO2
NH-R

25. Role of Cytochrome P-450 Monooxygenases in Oxidative Biotransformation
General Equation describing the oxidation of many
xenobiotics (R-H) forming a metabolite (R-OH)
R-H + NADPH + O2 + H+
R-OH + NADPH + H2 O
Reducing
agent
Molecular O2
substrate
Mixed Function in the biotransformation with Monooxygenases
Requires both molecular and a reducing agent
Enzyme responsible for transferring an Oxygen atom to the substrate
is called Cytochrome P-450

26. What is Cytochrome P-450 structure Important features:
Plays a vital role in oxidation of
lipophilic xenobiotics
metabolize almost unlimited number
of diverse substrates by a variety of
oxidative transformations.
-located in the endoplasmic reticulum

27. …to be continued next meeting
…to be continued next meeting. Please prepare ½ crosswise for a short quiz…
Good Luck!

28. General Pathways of Drug Metabolism
Phase II or Conjugation Reaction
* Glucoronic Acid Conjugation
* Sulfate Conjugation
* Conjugation with Glycine, Glutamine and
other Amino Acids
* Glutathione or Mercapturic Acid Conjugation
* Acetylation
* Methylation

29. Factors Affecting Dug Metabolism
Age Difference
Species and Strain Differences
Hereditary or Genetic Factors
Sex Differences
Enzyme Induction
Enzyme Inhibition
Metabolism
Pharmacologically active Metabolites

30. A. Age
Undeveloped or deficient oxidative and conjugative enzyme causes a reduced metabolic capability of newborns.
Metabolic reacion increases after after birth or when approaches adult levels
Influence of age on drug metabolism is seen on the duration of action of the drug (sleep time) in nweborn and adults.
Example: newborn mice sleeps 6 hours
adult sleeps fewer than 6 minutes if given the
same dose of 10mg/kg of body weight
In Humans – half life of tolbutamide is 8 hours while in infants it is 40 hours.

31. B. Species 7 Strain Differences