Cytochrome P450 (CYP): Isoforms, Inducers, Inhibitors, and Clinical Interactions

1. General Information

• Cytochromes P450 are a superfamily of heme-containing monooxygenases; a total of ~57 isoforms in humans.
• Families CYP1, CYP2, and CYP3 are of the greatest importance in xenobiotic biotransformation.
• Metabolic phases: Phase I (oxidation/reduction/hydrolysis — often CYP) → Phase II (conjugation — glucuronidation, sulfation, acetylation, glutathione).
• Genetic polymorphism determines individual differences.
• Interactions via CYPs are one of the leading causes of medication errors and adverse reactions.

2. Key Isoforms

CYP3A4/3A5

• Metabolizes ~50% of drugs.
• Localization: liver + intestine (significant presystemic elimination).
• Substrates: statins (atorvastatin, simvastatin), Ca²⁺ channel blockers, protease inhibitors, macrolides, azoles, tacrolimus/cyclosporine, alprazolam, midazolam, sildenafil, quinidine, amiodarone.
• Inhibitors: clarithromycin, erythromycin, itraconazole, ketoconazole, voriconazole, ritonavir, grapefruit juice, cobicistat.
• Inducers: rifampicin, phenytoin, carbamazepine, St. John's wort, efavirenz, glucocorticoids (to a lesser extent).

CYP2D6

• ~25% of drugs; not inducible.
• High degree of polymorphism: ultrarapid (1–10% of Europeans, 30% of Ethiopians), rapid (normal), intermediate, poor (5–10% of Europeans).
• Substrates: β-blockers (metoprolol, propranolol), antidepressants (fluoxetine, paroxetine, venlafaxine), antipsychotics (haloperidol, risperidone), codeine/tramadol (prodrugs!), tamoxifen (prodrug), dextromethorphan.
• Inhibitors: paroxetine, fluoxetine, bupropion, quinidine, terbinafine.

CYP2C9

• Substrates: warfarin (S-isomer), phenytoin, NSAIDs (ibuprofen, celecoxib, diclofenac), losartan, glimepiride, glipizide.
• Inhibitors: fluconazole, amiodarone, trimethoprim/sulfamethoxazole, miconazole.
• Inducers: rifampicin, carbamazepine.
• Polymorphisms *2, *3 → poor metabolizers → ↑ bleeding risk at standard warfarin doses.

CYP2C19

• Substrates: clopidogrel (prodrug!), PPIs (omeprazole, esomeprazole), diazepam, phenytoin, citalopram, escitalopram, voriconazole.
• Inhibitors: omeprazole, esomeprazole, fluconazole, fluoxetine.
• Inducers: rifampicin.
• Polymorphisms: poor metabolizers (15–20% of Asians, 3–5% of Europeans) — clopidogrel is ineffective; ↓ conversion to active thiol metabolite.

CYP1A2

• Substrates: caffeine, theophylline, clozapine, olanzapine, duloxetine, tizanidine, melatonin.
• Inhibitors: ciprofloxacin, fluvoxamine, oral contraceptives, cimetidine.
• Inducers: smoking (polycyclic aromatic hydrocarbons), omeprazole, carbamazepine, cruciferous vegetables.
• Smokers: clozapine and olanzapine doses are 50% higher; smoking cessation increases toxicity risk.

CYP2E1

• Substrates: paracetamol (conversion to the hepatotoxic NAPQI), ethanol, isoniazid, inhalational anesthetics (halothane).
• Inducers: chronic ethanol intake, isoniazid, biliary obstruction.
• Explains the hepatotoxicity of paracetamol in chronic alcoholics.

CYP2B6

• Substrates: efavirenz, bupropion, methadone, ketamine, cyclophosphamide.
• Polymorphisms affect antiretroviral therapy efficacy.

3. Clinically Significant Interactions

4. Grapefruit juice

• Grapefruit furanocoumarins are irreversible intestinal CYP3A4 inhibitors (effect lasts 24–72 h).
• They increase the bioavailability of simvastatin, atorvastatin, amlodipine, tacrolimus, cyclosporine, sildenafil, buspirone, amiodarone.
• Concurrent use is contraindicated during therapy with narrow therapeutic index CYP3A4 substrates.

5. Prodrugs and metabolism

• Codeine → morphine (CYP2D6).
• Tramadol → O-desmethyltramadol (CYP2D6).
• Clopidogrel → active thiol (CYP2C19 + 3A4).
• Tamoxifen → endoxifen (CYP2D6).
• Cyclophosphamide → alkylating metabolites (CYP2B6, 3A4).
• Losartan → EXP3174 (CYP2C9).
• Note: prodrugs are ineffective in poor metabolizers, and toxic in ultrarapid metabolizers.

6. Pharmacogenetics

• CYP2D6: > 100 variants; classified into PM (poor), IM (intermediate), EM (extensive/normal), UM (ultrarapid).
• CYP2C19: *2, *3 — poor; *17 — ultrarapid (↓ PPI efficacy).
• CYP2C9: *2, *3 — reduce activity → lower warfarin dose.
• VKORC1 — warfarin target, contributes to dose variability.
• Testing according to CPIC and FDA recommendations (pharmacogenetic tables in PharmGKB).

7. CYP inhibitors — classification

• Strong (↑ AUC ≥ 5×): clarithromycin, itraconazole, ketoconazole, ritonavir, cobicistat, grapefruit.
• Moderate (AUC ↑ 2–5×): erythromycin, fluconazole, diltiazem, verapamil.
• Weak (AUC ↑ 1.25–2×): cimetidine, ciprofloxacin.
• Mechanism-based (suicide) inhibitors — irreversible inactivation (clarithromycin, grapefruit, ritonavir).

8. CYP inducers

• Strong (↓ AUC ≥ 80%): rifampicin, phenytoin, carbamazepine, St. John's wort, enzalutamide.
• Moderate: efavirenz, modafinil, bosentan, barbiturates.
• Induction is a slow effect (7–14 days), requiring enzyme accumulation.
• After inducer discontinuation — substrate levels drop within 2–4 weeks.

9. Special situations

• Pregnancy: ↑ CYP3A4, 2D6 → dose adjustments may be required (phenytoin, labetalol).
• Pediatric patients: maturation of CYP isoforms during the first year; mg/kg doses are not equivalent to adults.
• Elderly patients: reduced hepatic blood flow and activity of certain CYPs → ↓ starting doses.
• Liver failure: decreased CYP, adjust according to Child-Pugh.
• Critical illness: CYP variability, inflammation suppresses CYP3A4.

10. Clinical guidelines

• Drug interaction checking via databases (UpToDate Lexicomp, Medscape, Drugs.com, clinical pharmacists).
• Minimization of polypharmacy.
• Pharmacogenetic testing in chronic therapy with narrow therapeutic index drugs (warfarin, clopidogrel, TCAs, antiepileptics).
• Patient education on avoiding grapefruit and St. John's wort.

11. FAQ

Why is codeine contraindicated in children < 12 years of age?
Variable CYP2D6; rapid conversion to morphine in ultrarapid metabolizers carries a risk of respiratory depression. FDA black-box warning since 2013.

How to check for interactions?
Databases: UpToDate Lexicomp, Drugs.com, Medscape. In Russia — Vidal, State Register of Medicines (GRLS). Consult a clinical pharmacologist for complex regimens.

Which PPIs are best combined with clopidogrel?
Pantoprazole and rabeprazole have lower CYP2D19/CYP2C19 inhibition. Omeprazole, esomeprazole — ↓ clopidogrel efficacy (most clinically significant).

Can standard doses of clozapine be prescribed to smokers?
No; smoking induces CYP1A2 → clozapine and olanzapine doses are 30–50% higher than in non-smokers. Upon smoking cessation — downward dose adjustment.

Why is rifampicin dangerous in combinations?
Potent inducer of CYP3A4, 2C9, 2C19, 1A2 + P-gp → ↓ levels of many drugs (warfarin, contraceptives, ARVs, tacrolimus). Always check interactions when prescribing.

See also: Pharmacokinetics · Anticoagulants · Antidepressants · Antibiotics · Pharmacology Catalog