Core16: Phases of drug biotransformation

⚙️ High-yield / 要点：Biotransformation converts drugs from hydrophobic → hydrophilic to facilitate elimination. Phase 1 = oxidation/reduction/hydrolysis, Phase 2 = conjugation.

Definition / 定義

• Biotransformation = metabolic conversion of substances entering the body.
• Main purpose: make molecules more hydrophilic / polar so they can be eliminated more easily.

Consequences of metabolism / 代謝の結果

Outcome	Meaning	Example
Inactive metabolite	Drug loses pharmacological activity	Midazolam
Active metabolite	Metabolite also has pharmacological activity	Diazepam
Prodrug activation	Drug becomes active only after metabolism	Ramipril, perindopril
Toxic metabolite	Metabolism creates harmful intermediate	Acetaminophen → NAPQI

Acetaminophen toxicity / アセトアミノフェン中毒

• Acetaminophen can form NAPQI / N-acetyl-p-benzoquinone imine.
• NAPQI is reactive and hepatotoxic/nephrotoxic.
• Normally detoxified by conjugation and cleared.
• In overdose, detoxification is overwhelmed → liver/kidney injury.

Phase 1 reactions / 第I相反応

• Main reactions:
  • Oxidation
  • Reduction
  • Hydrolysis
• Product is usually:
  • More polar.
  • More water-soluble.
  • More reactive.
• Microsomal reactions:
  • Mainly cytochrome P450 in smooth ER.
  • Major sites: liver; also GI, kidney, lung.
  • Important CYPs: CYP3A4, CYP2D6, CYP2C9.
• Non-microsomal reactions:
  • Hydrolysis.
  • Monoamine oxidase.
  • Alcohol metabolism.

Phase 2 reactions / 第II相反応

• Main process: conjugation by transferase enzymes.
• Adds polar groups such as:
  • Glucuronate
  • Acetate
  • Glutathione
• End product is usually:
  • More polar.
  • Less lipophilic.
  • Easily excreted.
• Important exception:
  • Morphine-6-glucuronide is more active than morphine.

Pharmacogenetics / 薬理遺伝学

• CYP450 activity varies between people.
• Important phenotypes:
  • Poor metabolizers
  • Extensive metabolizers
• These differences affect efficacy, toxicity, and dose requirements.

Remember / 覚え方

• Phase 1 = functionalize
• Phase 2 = conjugate
• Hydrophobic → hydrophilic → excretion
• Prodrugs need metabolism; acetaminophen overdose creates toxic NAPQI