Chapter 2  ·  Module 3  ·  Visual Summary

Metabolism and Biotransformation

Phase one and two reactions, cytochrome P450 isoforms, enzyme interactions, and pharmacogenomics

Key Cytochrome P450 Isoforms — Substrates, Inhibitors, and Inducers

Isoform Key Substrates Key Inhibitors Key Inducers
CYP3A4 Statins (simvastatin, lovastatin, atorvastatin), cyclosporine, tacrolimus, benzodiazepines, calcium channel blockers, many others (~50% of drugs) Azole antifungals, macrolide antibiotics, ritonavir, grapefruit (intestinal) Rifampin, carbamazepine, phenytoin, phenobarbital, St. John's wort
CYP2C9 Warfarin (S-enantiomer), NSAIDs, phenytoin, sulfonylureas Fluconazole, amiodarone, metronidazole Rifampin, carbamazepine
CYP2C19 PPIs (omeprazole, pantoprazole), clopidogrel (activation), diazepam, SSRIs Omeprazole, fluconazole, fluvoxamine Rifampin
CYP2D6 Codeine (activation to morphine), tramadol, TCAs, SSRIs, metoprolol, tamoxifen (activation) Fluoxetine, paroxetine, bupropion, quinidine None clinically significant
CYP1A2 Theophylline, clozapine, caffeine, olanzapine Fluvoxamine, ciprofloxacin Cigarette smoking, omeprazole
Acetaminophen toxicity: CYP2E1 converts acetaminophen → N-acetyl-para-benzoquinone imine (NAPQI), a reactive electrophile. Normally conjugated by glutathione. In overdose or glutathione depletion (fasting, alcoholism): NAPQI accumulates → hepatocyte necrosis. Antidote: N-acetylcysteine (replenishes glutathione).

Phase Two Reactions — Conjugation

Glucuronidation (UGT enzymes)

Major conjugation pathway

  • Attaches glucuronic acid → water-soluble conjugate, renally/biliarily excreted
  • Morphine-6-glucuronide: active opioid metabolite — accumulates in renal failure
  • Neonatal deficiency: UGT immature at birth
  • Chloramphenicol gray baby syndrome: drug accumulation → cardiovascular collapse

Acetylation (NAT2 enzyme)

Slow vs. rapid acetylator phenotype

  • Substrates: isoniazid, hydralazine, procainamide, dapsone
  • Slow acetylators (40–70% European/Middle Eastern): more drug accumulation
  • Isoniazid: slow acetylators → more neuropathy, hepatotoxicity risk
  • Hydralazine/procainamide: slow acetylators → more drug-induced lupus

Hepatic Clearance — Low-Extraction vs. High-Extraction

Feature Low-Extraction (Capacity-Limited) High-Extraction (Flow-Limited) Clinical Implication
Extraction ratio < ~0.3 > ~0.7 Determines first-pass magnitude
Rate-limiting factor Enzyme activity Hepatic blood flow Dictates what changes clearance
Enzyme inhibitor effect Large rise in plasma level Smaller effect Inhibitor interactions most dangerous for low-extraction drugs
Reduced blood flow (cirrhosis, hypotension) Minimal effect Major rise in plasma level Reduce high-extraction drug doses in cirrhosis or low-output states
Examples Warfarin, phenytoin, theophylline Lidocaine, morphine, propranolol

Enzyme Induction vs. Inhibition

Enzyme Induction

Increased enzyme expression → faster metabolism

  • Onset: gradual (1–3 weeks); offset: gradual after stopping
  • Effect: lower plasma concentrations of substrates → treatment failure
  • Rifampin: most potent inducer (CYP3A4, 2C9) — reduces substrate levels 80–90%
  • Others: carbamazepine, phenytoin, phenobarbital, St. John's wort
  • Key interactions: rifampin + warfarin (loss of anticoagulation), rifampin + oral contraceptives (failure), St. John's wort + cyclosporine (rejection)

Enzyme Inhibition

Decreased enzyme activity → slower metabolism

  • Onset: rapid (hours to days); offset: rapid (except mechanism-based)
  • Effect: higher plasma concentrations of substrates → toxicity
  • CYP3A4: azole antifungals, macrolides, ritonavir
  • CYP2C9: fluconazole, amiodarone — potentiate warfarin → bleeding
  • CYP2D6: fluoxetine, paroxetine — raise TCA levels, abolish codeine analgesia
  • Mechanism-based (irreversible): grapefruit (intestinal CYP3A4, 24–72 h), erythromycin, clarithromycin

Pharmacogenomics — Metabolizer Phenotypes and Prodrug Activation

Drug CYP Poor Metabolizer Effect Ultra-Rapid Metabolizer Effect Key Clinical Action
Codeine 2D6 No analgesia (no morphine generated) Morphine toxicity, respiratory depression — FDA black box Avoid in breastfeeding mothers; avoid CYP2D6 inhibitors with codeine
Clopidogrel 2C19 Inadequate platelet inhibition → stent thrombosis — FDA black box Possibly greater effect (uncertain clinical significance) Consider prasugrel or ticagrelor in poor 2C19 metabolizers; prefer pantoprazole over omeprazole with clopidogrel
Tamoxifen 2D6 Low endoxifen → higher breast cancer recurrence risk Higher endoxifen (uncertain benefit) Avoid fluoxetine/paroxetine (potent CYP2D6 inhibitors) with tamoxifen; use sertraline or venlafaxine if antidepressant needed
Warfarin 2C9 Reduced clearance → elevated INR, bleeding risk at standard doses Possible resistance Use lower doses in 2C9 poor metabolizers; incorporate genotype in dosing algorithm
Remember: For prodrugs (codeine, clopidogrel, tamoxifen), the usual rules reverse. A CYP2D6 inhibitor added to codeine does not protect from toxicity — it eliminates efficacy by preventing morphine formation. Adding fluoxetine to a tamoxifen regimen does not reduce side effects — it may reduce cancer protection.