Metabolic changes of drugs and related organic compounds
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METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS. Chapter 2. Roselyn Aperocho-Naranjo USPF-College of Pharmacy [email protected] www.roselynnaranjo.vze.com. METABOLISM. > chemical reaction that occur in the body to maintain life

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METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS

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Metabolic changes of drugs and related organic compounds

METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS

Chapter 2

Roselyn Aperocho-Naranjo

USPF-College of Pharmacy

[email protected]

www.roselynnaranjo.vze.com


Metabolism

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.


Background

Drug molecules easily diffuse through membranes

Reach the target site & produce a pharmacologic response

Most drugs that enter the body are lipid-soluble

Metabolized in the liver

Background


Background1

Background

Of Drugs or Xenobiotics

Metabolism plays a central role in the

Elimination


Sites of drug biotransformation

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


General pathways of drug metabolism

General Pathways of Drug Metabolism

> Phase I or Functionalization

Reactions includes:

* Oxidative Reaction

* Reductive Reaction

* Hydrolytic Biotransformation


General pathways of drug metabolism1

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


General summary of phase i and phase ii metabolic pathways

General Summary of Phase I and Phase II Metabolic Pathways

A. Oxidation Reactions


General summary of phase i and phase ii metabolic pathways1

General Summary of Phase I and Phase II Metabolic Pathways

A. Oxidation Reactions


Oxidative reactions

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


Arene oxides

Arene Oxides

A. Spontaneous arrangement

R

I

R

I

R

I

H

I

OH

I

O

O

H

Arene oxide

Arenols


Example of oxidation reaction

Example of Oxidation Reaction

Allylic Hydroxylation of Marijuana

(Δ1 tetra Hydrocannabinol)

CH3

CH2OH

CH3

CH3

CH3

CH3


Example of oxidation reaction1

Example of Oxidation Reaction

Allylic Hydroxylation of Marijuana

(Δ1 tetra Hydrocannabinol)

(CH3)

H

H-C-OH

H

H

H-C-H

I

(CH2OH)


Example of oxidation reaction2

CH2OH

CH3

CH3

7- Hydroxy Δ1 tetra Hydrocannabinol

Example of Oxidation Reaction

1. Allylic Hydroxylation of Marijuana

(Δ1 tetra Hydrocannabinol)

CH3

CH3

CH3


Example of oxidation reaction3

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


Example of oxidation reaction4

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


Oxidation reaction

CH2OH

CH3

CHO

COOH

CH3

7- Hydroxy Δ1 tetra Hydrocannabinol

CH3

CH3

CH3

CH3

Oxidation Reaction

  • Oxidation of Benzyclic Carbon Atoms

    - the primary alcohol are often oxidized to form aldehydes and carboxyllic acids

    CH2OH –------ CHO ------------- COOH


Oxidation reaction1

H

H

OH

OH

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

H

3-hydroxydiazepam

oxazepam

diazepam


Oxidation reaction2

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


Important therapeutic agents that undergo aromatic hydroxylation

Important Therapeutic Agents that undergo Aromatic Hydroxylation

  • Propranolol Phenobarbital

back


Important therapeutic agents that undergo aromatic hydroxylation1

Important Therapeutic Agents that undergo Aromatic Hydroxylation

  • Phenytoin Phenylbutazone


Important therapeutic agents that undergo aromatic hydroxylation2

Important Therapeutic Agents that undergo Aromatic Hydroxylation

  • Ethinylestradiol Warfarin


Important therapeutic agents that undergo aromatic hydroxylation3

Important Therapeutic Agents that undergo Aromatic Hydroxylation

  • Amphetamine


Important therapeutic agents that undergo aromatic hydroxylation4

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


Role of cytochrome p 450 monooxygenases in oxidative biotransformation

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


What is cytochrome p 450

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


Metabolic changes of drugs and related organic compounds

…to be continued next meeting. Please prepare ½ crosswise for a short quiz…

Good Luck!


General pathways of drug metabolism2

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


Factors affecting dug metabolism

Factors Affecting Dug Metabolism

  • Age Difference

  • Species and Strain Differences

  • Hereditary or Genetic Factors

  • Sex Differences

  • Enzyme Induction

  • Enzyme Inhibition

  • Metabolism

  • Pharmacologically active Metabolites


A age

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.


B species 7 strain differences

B. Species 7 Strain Differences


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