PharmacologyTier 1Medical Sciences concept

CYP450-mediated drug-drug interactions

Core concept

Phase I (CYP450 oxidation) -> phase II (conjugation) -> excretion
Two directions of interaction, with completely different time courses
- Inhibition - competitive, immediate. Effect appears within 1-2 doses; magnitude limited by the affected drug's half-life
- Induction - requires new enzyme synthesis. Onset over 1-2 weeks, offset over 2-4 weeks after stopping
The direction of the clinical error depends on prodrug status
- Active drug + inhibitor -> toxicity
- Prodrug + inhibitor -> loss of effect (codeine, clopidogrel, tamoxifen)

Isoenzyme	Key substrates	Inhibitors	Inducers
3A4 (~50% of drugs)	Statins (simva, atorva), calcium channel blockers, ciclosporin, tacrolimus, midazolam, DOACs, macrolides, amiodarone, oestrogens, antiretrovirals	Azoles, clarithromycin/erythromycin, protease inhibitors, diltiazem, verapamil, grapefruit	Rifampicin, carbamazepine, phenytoin, phenobarbital, St John's wort
2C9	Warfarin (S-isomer), phenytoin, NSAIDs, sulfonylureas	Metronidazole, fluconazole, amiodarone, cotrimoxazole, valproate	Rifampicin, carbamazepine
2C19	Clopidogrel (prodrug), PPIs, diazepam	Omeprazole/esomeprazole, fluvoxamine, fluconazole	Rifampicin
2D6	Codeine/tramadol (prodrugs), tamoxifen (prodrug), metoprolol, TCAs, risperidone	Fluoxetine, paroxetine, bupropion, quinidine, duloxetine	Not inducible
1A2	Clozapine, theophylline, caffeine	Fluvoxamine, ciprofloxacin	Smoking, charcoal-grilled food
2E1	Paracetamol (to NAPQI), ethanol		Chronic alcohol, isoniazid

Mnemonics: inhibitors "SICKFACES.COM"; inducers "CRAP GPS" (Carbamazepine, Rifampicin, Alcohol chronic, Phenytoin, Griseofulvin, Phenobarbital, Sulfonylureas, St John's wort)
Simvastatin + clarithromycin -> rhabdomyolysis - withhold the statin for the antibiotic course; the classic examinable pair
Warfarin + metronidazole, fluconazole, cotrimoxazole or amiodarone -> INR spike; warfarin + rifampicin or carbamazepine -> INR collapse
Verapamil and diltiazem inhibit both CYP3A4 and P-gp -> raise warfarin, digoxin, DOACs, statins, ciclosporin
Amiodarone inhibits 3A4, 2C9 and P-gp, and has a 50-day half-life - the interaction persists for months

Toxicity from an inhibitor appears in days; failure from an inducer appears in weeks and is silent - no test flags it unless you are monitoring (INR, tacrolimus level)
Stopping an inducer is as dangerous as starting one - tacrolimus, warfarin and antiepileptic levels rise over the following fortnight
Fixed traps worth memorising
- Rifampicin + oral contraceptive -> contraceptive failure
- St John's wort + tacrolimus/ciclosporin -> graft rejection; + DOAC -> thrombosis
- Grapefruit + simvastatin, or + tacrolimus -> large exposure rise
- Fluvoxamine or ciprofloxacin + clozapine -> clozapine toxicity
- Stopping smoking -> CYP1A2 de-induction -> clozapine and theophylline levels rise
Check the interaction whenever a short course (antibiotic, antifungal) is added to a narrow-therapeutic-index drug
Enzyme induction is not always harmful - it is the mechanism of rifampicin-induced pruritus relief in cholestasis

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