8 Drug Metabolism Phase 1 and 2 reactions

Drug Metabolism Overview

  • Involves two major phases: Phase I and Phase II reactions.

    • Phase I Reactions: Functionalization reactions (oxidation, hydroxylation, etc.).

    • Phase II Reactions: Conjugation reactions (glucuronidation, acetylation, etc.).

  • Key functions: Convert drugs (xenobiotics) into more hydrophilic metabolites for elimination.

Phase I Reactions

  • Key Enzymes: Cytochrome P450s (CYPs).

  • Purpose: Introduce functional groups to drugs (e.g., -OH, -COOH).

  • Examples:

    • Hydroxylation of drugs (e.g., Metoprolol, Carvedilol).

    • Activation of certain prodrugs (e.g., irinotecan).

  • Metabolism routes often lead to drug inactivation.

Phase II Reactions

  • Main Enzymes: UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), N-acetyltransferases (NATs).

  • Purpose: Attach a hydrophilic moiety to the drug or metabolite.

  • Results in higher molecular weight and water solubility, aiding in drug excretion.

  • Specific conjugation outputs include glucuronide, sulfate, acetyl, and methyl derivatives.

Drug Metabolism Sites

  • Primary site for Phase I and II reactions: Liver.

  • Other sites: Plasma, lungs, gastrointestinal tract.

  • First-Pass Metabolism: Oral drugs undergo metabolism before systemic circulation, impacting bioavailability.

Importance of Drug Binding

  • CYP enzymes bind to drugs, influencing their metabolism and therapeutic effects.

  • Drug interactions can occur due to competition for CYP enzymes (e.g., Grapefruit juice and CYP3A4).

Clinical Relevance

  • Paracetamol (Acetaminophen): Primarily metabolized via glucuronidation and sulfation.

    • Overdose risks leading to hepatotoxicity via N-acetyl-p-benzoquinone imine (NAPQI).

    • Management includes N-acetylcysteine to replenish glutathione.

  • Methylation: Catalyzed by methyltransferases like COMT and TPMT, affecting drugs like 6-mercaptopurine.

Summary of Key Enzymes and Pathways

  • Phase I:

    • CYP3A4: Most abundant; metabolizes 30-50% of clinically used drugs.

    • Phase II:

      • UGT: Major role in glucuronidation.

      • SULT: Major role in sulfation.

      • NAT: Involves N-acetylation reactions.

Conclusion

  • Understanding drug metabolism is crucial for predicting drug behavior in the body, interactions, and clinical outcomes.