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.