MedChem Discussion Nov 6, 2023

Introduction to Drug Metabolism

  • Focus on Phase II Metabolism

Xenobiotic Metabolism

  • Three main processes: Absorption, Metabolism, Excretion

  • Phases of Metabolism:

    • Phase I (Functionalization)

      • Involves oxidation, reduction, or hydrolysis.

      • Enzymes include:

        • Cytochrome P450 (CYP)

        • Flavin-containing monooxygenase

        • Dehydrogenase

        • Esterases

      • Results in more polar metabolites.

    • Phase II (Conjugation reactions)

      • Involves conjugation, which improves water solubility and excretion.

      • Enzymes include:

        • Glutathione transferase (GST)

        • UDP-glucuronyl transferase (UGT)

        • Sulfotransferase (SULT)

        • Acetyltransferase

        • Methyltransferase

Human CYP450 Enzymes

  • Major isoforms and their abundance:

    • CYP3A4: 23% contribution to drug metabolism (50% hepatic abundance)

    • Other notable isoforms:

      • CYP2E1 (12%)

      • CYP2D6 (2%)

      • CYP2C9 (20%)

      • CYP2C8 (14%)

      • CYP2C19 (4%)

      • CYP2A6 (15%)

      • CYP1A2 (10%)

  • Role in drug metabolism varies by family and specific isoenzyme.

Properties of Phase II Metabolism

  • Conjugation of small polar endogenous molecules (e.g., glucuronic acid, sulfate, amino acids) to metabolites.

  • Enhances water-solubility to facilitate renal excretion.

  • Detoxification: Traps electrophilic substances using glutathione, protecting DNA, RNA, and proteins.

Enzymes Involved in Phase I and II Metabolism

  • Prominent Phase I enzymes:

    • CYP1A1/2, CYP2D6, CYP3A4 and others

  • Phase II enzymes:

    • UGT, SULT, NAT, GST

  • Each enzyme plays a crucial role in the metabolism of specific drugs.

Metabolic Reactions in Phase II

Conjugation Reactions

  • Glycination: Transfer of amino acids.

  • Glucuronidation: Addition of glucuronic acid operates via UDP-glucuronyl transferase.

  • Sulfation: Involves sulfate transfer via sulfotransferases, utilizing PAPS.

  • Acetylation: Uses Acetyl-CoA with N-acetyltransferases.

  • Methylation: Involves SAM (S-adenosyl methionine) for transferring methyl groups via methyltransferases.

Examples of Substrates for Conjugation

  • Glucuronidation: Effective on substrates such as acetaminophen, morphine.

  • Sulfation: Target substrates include a-methyldopa, albuterol.

  • Acetylation: Significant for drugs like procainamide, leading to detoxification.

Structural Alerts in Drug Metabolism

  • Common structural alerts could indicate susceptibility to metabolic activation.

    • Includes functional groups like anilines, phenols, and aromatics.

  • Identifies compounds potentially leading to toxic metabolites.

Key Takeaways

  • Drug metabolism comprises two major phases, evolving from functionalization (Phase I) to conjugation (Phase II).

  • Understanding specific enzymes and their substrates is crucial for predicting metabolic pathways and potential drug interactions.