Makindo Medical Notes

Drug metabolism is the process by which the body chemically alters drugs, facilitating their excretion. It primarily occurs in the liver and involves a series of enzymatic reactions that convert lipophilic drug molecules into more hydrophilic compounds that can be easily excreted.

Key Concepts

• Phases of Drug Metabolism:
  • Phase I (Functionalization Reactions):
    • Oxidation, reduction, hydrolysis reactions.
    • Introduce or uncover polar functional groups (e.g., -OH, -NH2).
    • Key enzymes: Cytochrome P450 monooxygenases (CYPs).
  • Phase II (Conjugation Reactions):
    • Conjugation of drug metabolites with endogenous substrates (e.g., glucuronic acid, sulfate, glutathione).
    • Increase water solubility to facilitate excretion.
    • Key enzymes: Transferases (e.g., UDP-glucuronosyltransferases, sulfotransferases).
• Sites of Drug Metabolism:
  • Liver: Primary site of drug metabolism.
  • Other Tissues: Kidneys, intestines, lungs, and skin also contribute.
• Factors Affecting Drug Metabolism:
  • Genetic Factors: Polymorphisms in drug-metabolizing enzymes can affect drug metabolism rates.
  • Age: Metabolic rate can vary with age; neonates and elderly may have slower metabolism.
  • Sex: Differences in enzyme activity can lead to sex-specific variations in drug metabolism.
  • Diet and Environment: Certain foods and environmental chemicals can induce or inhibit metabolic enzymes.
  • Disease States: Liver and kidney diseases can significantly impact drug metabolism.

Detailed Pathways

• Phase I Reactions:
  • Oxidation:
    • Cytochrome P450 enzymes (CYPs) catalyze oxidation reactions.
    • Example: CYP3A4 oxidizes many drugs, including statins and antibiotics.
  • Reduction:
    • Less common than oxidation.
    • Example: Reduction of nitro groups to amines.
  • Hydrolysis:
    • Esterases and amidases hydrolyze ester and amide bonds.
    • Example: Hydrolysis of procaine to para-aminobenzoic acid and diethylaminoethanol.
• Phase II Reactions:
  • Glucuronidation:
    • UDP-glucuronosyltransferases (UGTs) add glucuronic acid to substrates.
    • Example: Glucuronidation of bilirubin and acetaminophen.
  • Sulfation:
    • Sulfotransferases add sulfate groups to substrates.
    • Example: Sulfation of hormones, drugs like albuterol.
  • Glutathione Conjugation:
    • Glutathione-S-transferases (GSTs) conjugate glutathione to electrophilic compounds.
    • Example: Detoxification of reactive intermediates from acetaminophen metabolism.
  • Acetylation:
    • N-acetyltransferases (NATs) add acetyl groups to substrates.
    • Example: Acetylation of isoniazid and sulfonamides.

Clinical Relevance

• Drug Interactions:
  • Inhibition or induction of metabolic enzymes can lead to drug interactions.
  • Example: Grapefruit juice inhibits CYP3A4, increasing plasma levels of certain drugs.
• Pharmacogenomics:
  • Study of how genetic variations affect drug metabolism and response.
  • Example: CYP2D6 polymorphisms affect metabolism of codeine to morphine.
• Adverse Drug Reactions:
  • Accumulation of unmetabolized drugs or toxic metabolites can cause adverse effects.
  • Example: Toxicity from acetaminophen overdose due to formation of NAPQI, a reactive metabolite.
• Personalized Medicine:
  • Tailoring drug therapy based on individual metabolic profiles to optimize efficacy and minimize toxicity.

Summary

Drug metabolism is a critical process that converts lipophilic drugs into hydrophilic metabolites for excretion. It involves Phase I (functionalization) and Phase II (conjugation) reactions, primarily in the liver. Various factors, including genetics, age, sex, diet, and disease states, influence drug metabolism. Understanding these factors is essential for optimizing drug therapy, minimizing adverse effects, and advancing personalized medicine.