Drug Metabolism

Overview of Drug Metabolism

• Purpose of Drug Metabolism: After a drug exerts its effect, it needs to be metabolized for excretion.
• Metabolism Process:
  • Converts active drugs into inactive forms for excretion.
  • Can convert toxic substances to non-toxic metabolites.
  • Pro-drugs can be activated to exert therapeutic effects.

Metabolism Pathways

Phase 1 Metabolism

• Biotransformation: Involves phase one and phase two, but not always in sequence.
• CYP450 Enzymes:
  • Major enzymes for drug metabolism, primarily in the liver.
  • Key enzymes: CYP3A4 and CYP2D6.
  • Types of reactions: oxidation, reduction, hydrolysis.
  • Converts non-polar, lipid-soluble drugs to more polar, water-soluble forms.

Factors Affecting Phase 1 Metabolism

• Genetic Polymorphisms:
  • Influence enzyme activity, creating rapid or slow metabolizers.
  • Rapid metabolizers: decrease drug efficacy by increasing inactive metabolite.
  • Slow metabolizers: risk of toxicity due to high active drug levels.
• Drug Interactions:
  • CYP450 Inducers: Increase enzyme activity, reducing active drug levels.
  • CYP450 Inhibitors: Decrease enzyme activity, increasing active drug levels.
  • Important in polypharmacy situations.
• Physiological Factors:
  • Liver disease, age (infants/elderly) can decrease enzyme function leading to toxicity.
  • Example: Slow metabolism of codeine in infants can cause toxicity.

Phase 2 Metabolism

• Conjugation Reactions: Enhance excretion by increasing polarity and water solubility.
• Key Enzymes and Reactions:
  • Methylation, acetylation, sulfation, glucuronidation, glutathionylation.
  • Transferase enzymes add functional groups to metabolites.

Clinical Application

• Example: Clopidogrel and Omeprazole Interaction
  • Clopidogrel is a pro-drug metabolized by CYP450 to the active form.
  • Omeprazole inhibits CYP450, reducing clopidogrel’s activation, increasing heart attack risk.
• Impact of Phase 1 and Phase 2:
  • Drugs may undergo only one of the phases or both depending on specific metabolic needs.

Practice Problems

• Example Problem: Reaction types in drug metabolism (Phase 1 vs Phase 2).
  • Phase 1: Oxidation, reduction, hydrolysis.
  • Phase 2: Conjugation reactions (e.g., sulfation).

Conclusion

• Next Steps in Pharmacokinetics: Understanding drug excretion processes.

Complete the understanding of each phase and its factors to predict the pharmacokinetic behavior of drugs in patients with different metabolic capacities.