(4B) Drug Metabolism

Phase II Metabolism: Big Picture

Phase II is a conjugation reaction in which a drug or Phase I metabolite is coupled to an endogenous biochemical/cofactor.

Phase II Metabolism

3 required players:

1. Enzyme → usually a transferase

2. Substrate → drug or Phase I metabolite

3. Cofactor → provides the group transferred to the substrate

PROFESSOR EMPHASIS: If you see “transferase,”, think…

Phase II

Phase II products are:

• Often, but not always, highly ionized and readily excreted.

• Often, but not always, pharmacologically inactive.

• Limited to one Phase II reaction per molecule → afterward the molecule is generally excreted.

Phase 1 and 2 metabolism

important to understand facts

• Phase I does not always have to occur first.

• Some sufficiently polar drugs can proceed directly to Phase II.

• Some drugs may simply be excreted unchanged

Main functional groups used for Phase II (functional group already present on the drug/substrate)

• Phenols

• Alcohols

• Carboxylic acids

• These are the O/OH-containing groups he wants you most comfortable identifying.

• Amines and sulfhydryl groups can also participate, but Phase II reactions there are less common. For an amine, the professor said to first think about Phase I deamination.

Master Table — Phase II Conjugations

Glucuronic Acid Conjugation

Conjugation occurs through an…

conjugation can occur through an alcohol-type O or a carboxylic-acid O.

Glucuronic Acid Conjugation

Addition of glucuronic acid helps…

create/maintain ionization → ↑ water solubility and facilitates excretion.

Sulfate Conjugation

How conjugation occurs?

Sulfate from PAPS is transferred specifically to the phenolic OH.

Sulfate Conjugation

popularity?

Professor emphasized phenols occur frequently in drugs, making this one of the two major conjugations to know well.

Methylation

What COMT does?

• COMT specifically methylates the meta OH.

Methylation

For adrenergic compounds, COMT methylation is a…

highly inactivating mechanism

Glutathione Conjugation

Glutathione structure…

• Glutathione is a tripeptide made of:

  • Glutamate

  • Cysteine

  • Glycine

• The cysteine residue contains the group that attacks the electrophile.

Glutathione Conjugation

Professor Example

Acetaminophen

A minor CYP2E1 pathway can produce an electrophilic metabolite.

That electrophile can damage liver-cell proteins.

Glutathione attacks the electrophile instead → detoxification.

Glutathione Conjugation

What can be given when glutathione is inadequate and help deal with electrophilic metabolites?

N-acetylcysteine (Mucomyst)

Hydrolysis

Esters are…

• metabolically unstable

• hydrolyzed very quickly.

Hydrolysis

Ester reaction

Ester + esterase → carboxylic acid + alcohol

Pharmacogenomics

major definition to know

• EM = extensive metabolizer

• IM = intermediate metabolizer

• PM = poor metabolizer

• UM = ultra metabolizer

LOOK AT ALL EXAMPLES IN NOTES