U01.05.004 Drug metabolism

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Drugs are metabolized through Phase I and Phase II reactions, which serve to bioactivate or deactivate substances. Importantly:

Phase I and Phase II do not have to occur sequentially; either can occur first.
Phase I metabolism is often lost first in geriatric patients.
Slow acetylators are at higher risk for adverse drug effects due to decreased Phase II metabolism (e.g., isoniazid).

Phase I Reactions (Functionalization Reactions)

Enzyme system: Mostly CYP450-dependent
Processes:
- Oxidation
- Reduction
- Hydrolysis
Effect on drugs:
- Converts lipophilic drugs into slightly polar metabolites
- Metabolite may be active or inactive
Clinical relevance:
- Phase I activity declines with age
- Reactive oxygen metabolites may form → potential toxicity

Phase II Reactions (Conjugation Reactions)

Processes:
- Glucuronidation
- Acetylation
- Sulfation
- Methylation
Effect on drugs:
- Produces very polar, hydrophilic metabolites (except acetylated metabolites)
- Facilitates renal or biliary excretion
Clinical relevance:
- Slow acetylators have reduced metabolism → ↑ drug toxicity

Drug Metabolism Overview Table

Feature	Phase I (Functionalization)	Phase II (Conjugation)
Enzymes	CYP450, reductases, hydrolases	Transferases (UGT, NAT, SULT, MT)
Reaction type	Oxidation, reduction, hydrolysis	Glucuronidation, acetylation, sulfation, methylation
Polarity of metabolite	Slightly polar (active or inactive)	Very polar, hydrophilic (facilitates excretion)
Substrate type	Lipophilic drugs	Metabolites from Phase I or direct drug conjugation
Clinical notes	Decrease in the elderly; reactive oxygen species may form	Slow acetylators → higher drug toxicity

Excretion

Serum → urine or sweat
Bile → stool

Learning Objective:

Explain the differences between Phase I and Phase II drug metabolism, including enzymes, reaction types, metabolite polarity, and clinical relevance, such as age-related decline and slow acetylator effects.