Cytochrome P450 system

CYP450 Basics - The Body's Detox Crew

• Primary Role: A family of heme-containing enzymes, primarily in the liver and GI tract, that catalyze Phase I reactions (oxidation, reduction, hydrolysis).
• Function: Converts lipophilic drugs into more polar (hydrophilic) metabolites for easier renal excretion.
• Inducers: ↑ metabolism, leading to ↓ drug concentration and efficacy.
  • 📌 Phenytoin, Carbamazepine, Rifampin, Alcohol (chronic), Barbiturates, St. John's Wort (PCRABS).
• Inhibitors: ↓ metabolism, leading to ↑ drug concentration and potential toxicity.
  • 📌 Grapefruit, Protease Inhibitors, Azoles, Cimetidine, Macrolides, Amiodarone, Non-DHP CCBs (GPACMAN).

⭐ CYP3A4 is the most abundant isoform, metabolizing over 50% of clinically used drugs.

CYP450 Genetics - The Polymorphism Problem

• Genetic variations (polymorphisms) in CYP genes create enzymes with different activity levels, altering drug metabolism.
• This leads to varied patient responses to standard drug doses.

• Metabolizer Phenotypes:
  • Poor Metabolizers (PMs): ↓ or no enzyme activity. Risk of toxicity from active drugs.
  • Intermediate Metabolizers (IMs): ↓ enzyme activity.
  • Extensive Metabolizers (EMs): Normal enzyme activity.
  • Ultrarapid Metabolizers (UMs): ↑ enzyme activity due to gene duplication. Risk of therapeutic failure with active drugs.

⭐ Clopidogrel & CYP2C19: Clopidogrel is a pro-drug activated by CYP2C19. Poor metabolizers have a higher risk of cardiovascular events (e.g., stent thrombosis) due to therapeutic failure.

CYP450 Interactions - Accelerators & Brakes

• CYP450 Inducers (Accelerators): ↑ synthesis of CYP enzymes → ↑ drug metabolism → ↓ drug efficacy.

  • 📌 Mnemonic: Chronic alcoholics Steal Phen-Phen and Never Refuse Greasy Carbs
  • Chronic alcoholism, St. John's Wort, Phenytoin, Phenobarbital, Nevirapine, Rifampin, Griseofulvin, Carbamazepine.

• CYP450 Inhibitors (Brakes): ↓ enzyme activity → ↓ drug metabolism → ↑ drug concentration & risk of toxicity.

  • 📌 Mnemonic: CRACK AMIGOS
  • Cimetidine, Ritonavir, Amiodarone, Ciprofloxacin, Ketoconazole, Acute alcohol, Macrolides, Isoniazid, Grapefruit juice, Omeprazole, Sulfonamides.

⭐ Grapefruit juice is a classic inhibitor of CYP3A4, significantly ↑ levels of drugs like statins (e.g., atorvastatin, simvastatin), leading to myopathy risk.

Key Enzymes & Substrates - The Usual Suspects

• CYP3A4/5: Metabolizes ~50% of clinical drugs.
  • Substrates: Statins (Atorvastatin, Simvastatin), Calcium Channel Blockers, Benzodiazepines, Macrolides.
• CYP2D6: Highly polymorphic; variable patient response.
  • Substrates: β-blockers, Antidepressants (SSRIs, TCAs), Opioids (Codeine).
• CYP2C9:
  • Substrates: Warfarin (narrow therapeutic index), Phenytoin, NSAIDs.
• CYP2C19:
  • Substrates: Clopidogrel, Proton Pump Inhibitors (Omeprazole).
• CYP1A2:
  • Substrates: Theophylline, Caffeine.

⭐ Codeine, a prodrug, requires metabolism by CYP2D6 to its active form, morphine. Poor CYP2D6 metabolizers may experience little to no analgesic effect.

High‑Yield Points - ⚡ Biggest Takeaways

• The Cytochrome P450 system is the cornerstone of Phase I metabolism, primarily in the liver, making drugs more polar for excretion.
• CYP inducers (e.g., Rifampin, Phenobarbital) accelerate metabolism, potentially causing therapeutic failure by decreasing drug levels.
• CYP inhibitors (e.g., Ketoconazole, Grapefruit juice) slow metabolism, increasing drug levels and the risk of toxicity.
• For prodrugs, inducers increase active drug formation, while inhibitors decrease it.
• Genetic polymorphisms in CYP genes explain individual differences in drug efficacy and toxicity.
• CYP3A4 is the most abundant isoform, metabolizing >50% of drugs.