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Drug Metabolism Notes
Jul 17, 2024
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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.
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