Phase 1 and Phase 2 Metabolism

Phase 1 Metabolism

Introduction of a polar functional group or modification of an existing functional group in a drug molecule such that it becomes more polar

Types of Phase 1 Metabolism Reactions

1. Oxidation

2. Reduction

3. Hydrolysis

1. Oxidation

Introduction of OH

Enzymes: mixed-function oxidases, monooxygenases, cytochrome P450, association with reductase enzyme (contains NADPH - co-factor)

Oxidative Enzymes/Examples

- flavin-containing monooxygenases: nucleophilic atoms

- alcohol-dehydrogenases: alcohols to aldehydes and ketones

- aldehyde-dehydrogenases: aldehydes to carboxylic acids

2. Reduction

Reductions of aldehyde, ketone, nitro and azo groups observed

Enzymes: reductase

3. Hydrolysis Enzymes/Examples

Introduction of H2O

- esterases: esters

- petidases/amidases: amides

Chemical Hydrolysis: Specific base-assisted ester hydrolysis

nucleophilic attack of OH- on the electropositive ester carbon

Chemical Hydrolysis: Specific acid-assisted ester hydrolysis

protonation of carbonyl oxygen

Chemical Hydrolysis: General base-assisted ester hydrolysis

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Chemical Hydrolysis: General acid-assisted ester hydrolysis

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Chemical Hydrolysis: Nucleophilic catalysis

nucleophilic attack on carbonyl carbon

Chemical Hydrolysis: Metal ion catalysis

positively charged metal ions bind to oxygen atoms

Enzyme-catalysed hydrolysis

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Phase 2 Metabolism

Conjugation reactions in which a polar molecule is linked to a suitable functional group on a drug or one of its Phase 1 metabolites

Types of Phase 2 Metabolism Reactions

1. Glucuronic acid conjugation

2. Sulfate conjugation

3. Amino acid conjugation

4. Glutathione conjugation

5. Acetylation

6. Methylation

1. Glucuronic acid conjugation

- alcohols, phenols, carboxylic acids

Enzyme: glucuronyl transferase

2. Sulfate conjugation

- phenols, alcohols, amines

Enzyme: sulfotransferases

3. Amino acid conjugaion

- carboxylic acids

4. Glutathione conjugation

- electrophilic centre, alkyl halides, epoxides

Enzyme: glutathione transferase

5. Acetylation

- primary aromatic amines, sulfonamides

Enzyme: N-acetyl transferases

- less water soluble, but pharmacologically inactive

6. Methylation

- phenol, thiol, amino groups, N-containing heterocycles

Enzyme: methyltransferases

Co-factor: S-adenosyl methionine (SAME)

- less water soluble, but pharmacologically inactive