PHASE I METABOLISM REACTIONS (OXIDATION, REDUCTION, HYDROLYSIS)

Aromatic Hydroxylation (Oxidation)

An H is replaced by an OH group on a benzene ring to make a phenol

- This reaction happens in the para position (position opposite the site of substitution)

Benzylic Hydroxylation (Oxidation)

A carbon that is directly bonded to a benzene ring (in the benzylic position) and has Hs loses an H, which is replaced with an OH group

Aliphatic Hydroxylation (Oxidation)

1. ω Oxidation

2. ω-1 Oxidation

1. ω-Oxidation: the terminal (last) carbon in an alkyl chain loses an H that is replaced by an OH, and is further hydrolyzed into a carboxylic acid

2. ω-1 Oxidation: the penultimate (second-to-last) carbon in an alkyl chain loses an H that is replaced by an OH and is further hydrolyzed into a carboxylic acid.

Dealkylation of Ethers (Oxidation/O-Dealkylation)

The C adjacent to the O in the ether loses an H that is replaced by an OH. This generates an alcohol and a ketone (leaving group).

Dealkylation of Thioethers (Oxidation)

The C adjacent to the S in the thioether loses an H that is replaced by an OH. This generates a thiol and a ketone or aldehyde (leaving group).

Oxidation of 1° Alcohols

A primary alcohol (C has 2 H atoms) can be metabolized by an alcohol dehydrogenase, resulting in the loss of a water molecule (H2O). It can further be irreversibly metabolized by aldehyde oxidase to make a carboxylic acid as the final product.

Oxidation of 2° Alcohols

A secondary alcohol (C has 1 H atom) can be metabolized by an alcohol dehydrogenase, resulting in the loss of a water molecule (H2O) to form a ketone as the final product.

Dealkylation of 3° Amines (Oxidation/N-Dealkylation)

A carbon adjacent (alpha) to a tertiary amine loses an H, which is replaced by an OH; the resulting intermediate is further metabolized to yield a secondary amine and a ketone or aldehyde (leaving group).

Dealkylation of 2°Amines (Oxidation/N-Dealkylation)

A carbon adjacent (alpha) to a secondary amine loses an H, which is replaced by an OH; the resulting intermediate is further metabolized to yield a primary amine and a ketone or aldehyde.

- Whichever functional group is left on the larger part of the molecule is the product, while the functional group on the smaller molecule is the leaving group.

Oxidation of Primary Amines (N-Dealkylation)

A carbon adjacent (alpha) to a primary amine loses an H, which is replaced by an OH; the resulting intermediate is further metabolized to yield ammonia (leaving group) and a ketone or aldehyde.

- When the alpha carbon of a primary amine is tertiary (no Hs), the oxidation reaction will happen on the nitrogen. The amine will lose an H and will be replaced with an OH group.

Oxidative Dehalogenation

A halogen atom is removed from its adjacent carbon (alpha) and replaced by an OH. The final products are a carbonyl group (ketone or aldehyde) and a hydrogen halide (leaving group).

Reduction

- Carbonyl-containing groups like aldehydes and ketones gain an H atom and become alcohols.

Hydrolysis of Esters & Lactones

A water molecule (H2O) attacks the bond between the carbonyl and oxygen, resulting in a carboxylic acid and an alcohol as the final products.

- Fast-acting drugs are often esters

Hydrolysis of Amides & Lactams

A water molecule (H2O) attacks the bond between the carbonyl and nitrogen, resulting in a carboxylic acid and an amine as the final products.

- Slow-acting drugs are often amides