metabolic changes of drugs and related organic compounds roselyn aperocho-naranjo uspf-college of...

METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS

Roselyn Aperocho-NaranjoUSPF-College of Pharmacyrose_may26@yahoo.com

www.roselynnaranjo.vze.com

Chapter 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.

Background

Most drugs that enter the body are lipid-soluble

Metabolized in the liver

Drug molecules easily diffuse through membranes

Reach the target site & produce a pharmacologic response

Background

Metabolism plays a central role in the

EliminationElimination

Of Drugs or XenobioticsOf Drugs or Xenobiotics

Sites of Drug Biotransformation

2. Liver (hepatic metabolism or First Pass Effect

The most important organ in drug metabolism

1. Gastrointestinal TractAbsorb orally administered drugs

Some drugs may decrease Oral bioavailability

Lidocaine (ineffective)IsoproterenolMeperidineMorphine

NitroglycerinPentazocainePropoxyphene

Propranololsalicylamide

3. Blood CirculationAbsorb orally administered drugs

General Pathways of Drug Metabolism

> Phase I or Functionalization Reactions includes:

* Oxidative Reaction* Reductive Reaction* Hydrolytic

Biotransformation

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

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 REACTIONSA. Glucuronic Acid ConjugationB. Sulfate ConjugationC. Conjugation with Glycine, Glutamine and other Amino AcidsD. Glutathione or Mercapturic Acid ConjugationE. AcetylationD. Methylation

A. Oxidation Reactions

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 REACTIONSA. Glucuronic Acid ConjugationB. Sulfate ConjugationC. Conjugation with Glycine, Glutamine and other Amino AcidsD. Glutathione or Mercapturic Acid ConjugationE. AcetylationD. Methylation

A. Oxidation 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 OHArene Arene oxide

Arenol

Arene Oxides

R I

I O

Arene oxide

R I

O H

H

A. Spontaneous arrangement

R I

I OH

Arenols

Example of Oxidation Reaction

Allylic Hydroxylation of Marijuana (Δ1 tetra Hydrocannabinol)

CH3

CH3

CH3

CH2OH

CH3

CH3

HH-C-H I

HH-C-OH H

Example of Oxidation ReactionAllylic Hydroxylation of Marijuana (Δ1 tetra Hydrocannabinol)

(CH3)

(CH2OH)

Example of Oxidation Reaction1. Allylic Hydroxylation of Marijuana (Δ1 tetra Hydrocannabinol)

CH3

CH3

CH3

CH2OH

CH3

CH3

7- Hydroxy Δ1 tetra Hydrocannabinol

CH2OH

CH3

CH3

7- Hydroxy Δ1 tetra Hydrocannabinol

Example of Oxidation Reaction

COOH

CH3

CH3

2. Oxidation of THC to Carboxylic Acid derivative

7- Δ1 tetra Hydrocannabinoic Acid

3. Oxidation of THC to Carboxylic Acid derivative and Conjugation with Glucuronic Acid

COOR

CH3

CH3

Glucuronide conjugate

R – alkyl group

O ll C-O-

Example of Oxidation Reaction

Oxidation of Benzyclic Carbon Atoms - the primary alcohol are often oxidized to form aldehydes

and carboxyllic acids

CH2OH –------ CHO ------------- COOH

Oxidation Reaction

CH2OH

CH3

CH3

7- Hydroxy Δ1 tetra Hydrocannabinol

CH3

CH3

CHO

CH3

CH3

COOH

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.

Oxidation Reaction

OH

H

OH

H

HN-demethylation

diazepam 3-hydroxydiazepam oxazepam

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

Oxidation Reaction

Important Therapeutic Agents that undergo Aromatic Hydroxylation

Propranolol Phenobarbital

back

Important Therapeutic Agents that undergo Aromatic Hydroxylation

Phenytoin Phenylbutazone

Ethinylestradiol Warfarin

Important Therapeutic Agents that undergo Aromatic Hydroxylation

Important Therapeutic Agents that undergo Aromatic Hydroxylation

Amphetamine

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

General Equation describing the oxidation of manyxenobiotics (R-H) forming a metabolite (R-OH)

R-H + NADPH + O2 + H+ R-OH + NADPH + H2 O

Mixed Function in the biotransformation with MonooxygenasesRequires both molecular and a reducing agentEnzyme responsible for transferring an Oxygen atom to the substrate is called Cytochrome P-450

substrate Reducing agent

Molecular O2

What is Cytochrome P-450

structureImportant 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

…to be continued next meeting. Please

prepare ½ crosswise for a short quiz…

Good Luck!

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

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

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