METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS

1
METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC
COMPOUNDS
Chapter 2

• Roselyn Aperocho-Naranjo
• USPF-College of Pharmacy
• rose_may26_at_yahoo.com
• www.roselynnaranjo.vze.com

2
METABOLISM

• gt chemical reaction that occur in the body to
  maintain life
• gt allow organisms to grow and reproduce,
  maintain their structures, and respond to their
  environments
• gt 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
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 P
ropranolol salicylamide
1. Gastrointestinal Tract Absorb orally
administered drugs
3. Blood Circulation Absorb orally administered
drugs
6
General Pathways of Drug Metabolism

• gt 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
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
• (?1 tetra Hydrocannabinol)

CH3
CH2OH
CH3
CH3
CH3
CH3
13
Example of Oxidation Reaction
Allylic Hydroxylation of Marijuana (?1
tetra Hydrocannabinol)
(CH3)
H H-C-OH H
H H-C-H I
(CH2OH)
14
Example of Oxidation Reaction

• 1. Allylic Hydroxylation of Marijuana
• (?1 tetra Hydrocannabinol)

CH3
CH3
CH3
15
Example of Oxidation Reaction
2. Oxidation of THC to Carboxylic Acid derivative
CH2OH
COOH
CH3
CH3
CH3
CH3
7- ?1 tetra Hydrocannabinoic Acid
7- Hydroxy ?1 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

• Oxidation of Benzyclic Carbon Atoms
• - the primary alcohol are often oxidized to
  form aldehydes and carboxyllic acids
• CH2OH ------ CHO ------------- COOH

18
Oxidation Reaction

• Oxidation of C atoms ? to Carbonyls Imines
• - is a mixed function oxidase system which
  involve C atoms adjacent to carbonyl and imino
  (CN) group.

N-demethylation
H
3-hydroxydiazepam
oxazepam
diazepam
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. 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