Drug Metabolism Notes

Jul 17, 2024

Drug Metabolism

Introduction

  • Route of Administration: For example, oral administration.
  • Absorption: Drug absorbed across the GI tract.
  • First Pass Metabolism: Drug enters the portal system and undergoes metabolism before entering the bloodstream.
  • Distribution: Distributed through the circulatory system to various tissues.

Metabolism

  • Purpose: Convert active drugs into inactive forms for excretion, or convert toxic substances into non-toxic forms.
  • **Main Functions: **
    • Convert toxic substances into non-toxic metabolites.
    • Activate prodrugs (inactive form) into active drugs (e.g., valacyclovir to acyclovir).
    • Convert active drugs into inactive forms for easier excretion (urine, feces).
  • Primary Site: Liver, utilizing enzymes for metabolism.

CYP450 System

  • Location: Found in hepatocytes within the smooth endoplasmic reticulum and mitochondria.
  • Functions:
    • Oxidation
    • Reduction
    • Hydrolysis
  • Enzyme Types:
    • CYP3A4: Metabolizes ~50% of drugs.
    • CYP2D6: Metabolizes ~20-25% of drugs.

Enzyme Categories

  • Family: Denoted by the first number (e.g., CYP3).
  • Subfamily: Denoted by the letter (e.g., CYP3A).
  • Isozyme: Denoted by the last number (e.g., CYP3A4).

Metabolism Phases

Phase One: Biotransformation

  • Purpose: Convert non-polar, lipid-soluble drugs into polar, water-soluble forms.
  • Reactions:
    • Oxidation
    • Reduction
    • Hydrolysis
  • Consequences of Genetic Polymorphism:
    • Rapid Metabolizers: Decreased active drug levels; may need higher doses.
    • Slow Metabolizers: Increased active drug levels; risk of toxicity.

Drug Interactions

  • Inducers: Increase enzyme activity, convert more active drugs to inactive forms (e.g., rifampin).
  • Inhibitors: Decrease enzyme activity, increase active drug concentration (e.g., omeprazole), risk of toxicity.

Special Considerations

  • Liver Disease: Reduced efficacy of CYP450 enzymes, leading to higher active drug levels and potential toxicity.
  • Age: Both infants and elderly have decreased enzyme activity, leading to altered drug metabolism.

Phase Two: Biotransformation

  • Purpose: Further increase drug polarity and water solubility for excretion.
  • Enzymes: Transferases
    • Methylation
    • Acetylation
    • Sulfation
    • Glutathionylation
    • Glucuronidation
  • Outcome: Drug becomes highly polar and water-soluble, ready for excretion via biliary system or urine.
  • Term: Conjugation reactions

Practice Problems

  • Example: Clopidogrel (a prodrug) and omeprazole (CYP450 inhibitor).
    • Omeprazole inhibits CYP450, reducing conversion of clopidogrel to its active form, increasing risk of MI.
  • Another Example: Sulfation as a phase two reaction vs. oxidation, reduction, and hydrolysis in phase one.

Conclusion

  • Now that metabolism is covered, the next topic is drug excretion.