Drug metabolism phase 1 phase 2
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drug metabolism phase I phase II FDA cytochrome P450 conjugation
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Drug metabolism
Drug metabolism, mainly in the liver, converts lipid-soluble drugs into more water-soluble compounds so they can be eliminated in urine or bile. It occurs through Phase I and Phase II reactions. Lippincott Pharmacology summarizes the sequence.
Lippincott Illustrated Reviews: Pharmacology, p. 55.
Lippincott Illustrated Reviews: Pharmacology, p. 55.
| Feature | Phase I: Functionalization | Phase II: Conjugation |
|---|---|---|
| Main purpose | Introduces or exposes a functional group | Attaches a hydrophilic endogenous molecule |
| Typical reactions | Oxidation, reduction, hydrolysis | Glucuronidation, sulfation, acetylation, methylation, glutathione conjugation |
| Main enzymes | Mostly cytochrome P450 (CYP) enzymes | Transferase enzymes, e.g., UDP-glucuronosyltransferases |
| Result | Usually slightly more polar; may create an active, inactive, or toxic metabolite | Usually highly water-soluble and pharmacologically inactive |
| Clinical relevance | Major site of enzyme induction, inhibition, and genetic variation | Important in detoxification and drug elimination |
Phase I reactions
- Add or uncover groups such as -OH, -NH₂, or -SH.
- Usually catalyzed by the microsomal CYP450 enzyme system, especially in liver and intestinal mucosa.
- Common CYP isoenzymes: CYP3A4/5, CYP2D6, CYP2C9, CYP1A2.
- May:
- inactivate a drug
- activate a prodrug
- form a reactive or toxic metabolite
Examples
- Diazepam: oxidation by CYP enzymes
- Codeine: CYP2D6 converts it to active morphine
- Paracetamol: a small fraction undergoes CYP-mediated oxidation to toxic NAPQI
Phase II reactions
- Conjugate the drug or Phase I metabolite with a polar compound.
- Usually produces an inactive, water-soluble metabolite that is eliminated in urine or bile.
- A drug that is already sufficiently polar can undergo Phase II directly, without Phase I first.
Examples
- Paracetamol: glucuronidation and sulfation
- Morphine: glucuronidation
- Isoniazid: acetylation
- Toxic paracetamol metabolite NAPQI: glutathione conjugation
High-yield points
- Phase I is not always followed by Phase II, and Phase II can occur directly.
- Phase I does not always inactivate drugs. It can activate prodrugs or generate toxic metabolites.
- Enzyme inducers can reduce the effect of some drugs by increasing their metabolism, while inhibitors can raise drug levels and toxicity.
- The conventional “Phase III” refers to transporter-mediated export and excretion of drugs/metabolites.
Memory aid:
- Phase I = “Introduce” a functional group
- Phase II = “Integrate” a conjugate to make it water soluble
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