Core29: Pharmacokinetic drug interactions - at the level of metabolism

⚙️ High-yield / 要点：Metabolism-level PK interactions mainly involve CYP450 induction or inhibition. Induction lowers substrate levels; inhibition raises substrate levels.

Biotransformation overview / 代謝の全体像

• Biotransformation converts drugs from apolar → polar to support elimination.
• Phase I：oxidation, hydrolysis, reduction.
  • CYP450-dependent or CYP450-independent.
• Phase II：conjugation.
  • Glucuronide, sulfate, acetyl, methyl, glycol conjugates.

Major CYP contribution / 主なCYP

Isoenzyme	Approximate share of metabolized drugs
CYP3A4	~55%
CYP2D6	~30%
CYP2C9	~10%
CYP1A2	~2%

Enzyme induction / 酵素誘導

• Drug 1 increases transcription or decreases breakdown of metabolic enzymes.
• Enzyme activity increases → Drug 2 is metabolized faster.
• Result: drug level decreases and effect may become insufficient.
• Examples of inducers:
  • Phenobarbital.
  • Rifampicin/rifampin.
  • Smoking.
  • Carbamazepine.
  • Phenytoin.
• Example:
  • Rifampicin induces CYP3A4.
  • Oral contraceptives are broken down faster.
  • Risk: contraceptive failure / unintended pregnancy.

Enzyme inhibition / 酵素阻害

• Drug 1 inhibits metabolizing enzyme.
• Drug 2 breakdown becomes slower.
• Result: drug level increases and toxicity risk rises.
• Examples of inhibitors:
  • Ketoconazole.
  • Grapefruit.
  • Chloramphenicol.
  • Clarithromycin.
  • Nicardipine.
  • Verapamil.
  • Ritonavir.
  • Disulfiram.
• Example:
  • Disulfiram inhibits acetaldehyde dehydrogenase.
  • Alcohol → acetaldehyde accumulation → unpleasant symptoms.
  • Some cephalosporins can produce a disulfiram-like reaction; alcohol should be avoided.

Remember / 覚え方

• Induction = metabolism ↑ → drug level ↓
• Inhibition = metabolism ↓ → drug level ↑
• CYP3A4 handles many drugs