Pharmacokinetics 13 min read
Cytochrome P450 (CYP) enzymes
CYP enzymes are the primary drug-metabolising enzymes in the liver and gut. Understanding which enzymes metabolise which drugs — and what inhibits or induces them — is essential for predicting and managing drug-drug interactions.
What are CYP enzymes?
Cytochrome P450 (CYP) enzymes are a superfamily of haem-containing monooxygenases responsible for the oxidative metabolism of most drugs. They are concentrated in hepatocytes (liver) and enterocytes (intestinal wall), where they perform Phase I biotransformation — converting lipophilic parent drugs into more polar (water-soluble) metabolites for renal or biliary excretion.
The human genome encodes 57 CYP isoforms; approximately 6 isoforms (CYP3A4, 2D6, 2C9, 2C19, 1A2, 2B6) account for the metabolism of over 90% of marketed drugs. Their expression varies substantially between individuals due to genetic polymorphisms — the basis of pharmacogenomics — and can be further modified by co-administered drugs, diet, and environmental factors.
CYP3A4 (~50%) + CYP2D6 (~25%) + CYP2C9 (~15%) + CYP2C19 (~10%) + others → >95% of CYP-mediated drug metabolism
Major CYP Isoforms — Substrates, Inhibitors, Inducers
| Isoform | % of Drug Met. | Key Substrates | Key Inhibitors | Key Inducers |
|---|---|---|---|---|
| CYP3A4/5 | ~50% | Simvastatin, tacrolimus, cyclosporine, midazolam, nifedipine, amiodarone, many statins | Itraconazole, ketoconazole, ritonavir, clarithromycin, grapefruit | Rifampicin, carbamazepine, phenytoin, St John's Wort |
| CYP2D6 | ~25% | Codeine (→morphine), tramadol, metoprolol, haloperidol, fluoxetine, tamoxifen | Fluoxetine, paroxetine, bupropion, quinidine | Dexamethasone (weak) |
| CYP2C9 | ~15% | Warfarin (S-form), celecoxib, ibuprofen, glipizide, losartan, phenytoin | Fluconazole, amiodarone, metronidazole, sulfonamides | Rifampicin, carbamazepine |
| CYP2C19 | ~10% | Omeprazole, esomeprazole, clopidogrel (prodrug), diazepam, phenytoin | Omeprazole, fluconazole, fluvoxamine | Rifampicin, carbamazepine |
| CYP1A2 | ~5% | Theophylline, clozapine, olanzapine, caffeine, tizanidine | Fluvoxamine, ciprofloxacin (weak), enoxacin | Cigarette smoke, rifampicin, omeprazole |
| CYP2B6 | ~3% | Bupropion, methadone, efavirenz, ketamine | Ticlopidine, clopidogrel | Rifampicin, carbamazepine, phenobarbital |
Full classification: FDA DDI table ↗ · PharmGKB ↗ · Indiana University DDI database ↗
Inhibition vs Induction
CYP Inhibition
- Onset: Rapid — hours after adding inhibitor
- Effect: ↓ enzyme activity → ↑ substrate levels → toxicity risk
- Types: Reversible competitive; mechanism-based (irreversible)
- Offset: Resolves when inhibitor is cleared (half-lives)
- Example: Fluconazole + warfarin → ↑INR → bleeding
- Quantification: IC₅₀, Ki, R value (predicted DDI magnitude)
CYP Induction
- Onset: Slow — days to weeks (new enzyme synthesis)
- Effect: ↑ enzyme expression → ↓ substrate levels → efficacy loss
- Mechanism: Nuclear receptor activation (PXR, CAR, AhR)
- Offset: Resolves over days after stopping inducer
- Example: Rifampicin + OCP → contraceptive failure
- Quantification: EC₅₀, fold-induction, mRNA upregulation
High-Risk CYP DDI Examples
| Precipitant drug | Object drug | CYP | Interaction | Clinical consequence |
|---|---|---|---|---|
| Fluconazole | Warfarin | 2C9 inhibition | Inhibitor + substrate | ↑ INR → bleeding; reduce warfarin dose, monitor INR closely |
| Rifampicin | Cyclosporine | 3A4 induction | Inducer + substrate | ↓ cyclosporine levels → rejection; avoid combination or 3–5× dose increase |
| Clarithromycin | Simvastatin | 3A4 inhibition | Inhibitor + substrate | ↑ simvastatin AUC ~10-fold → rhabdomyolysis; switch to pravastatin or rosuvastatin |
| Carbamazepine | Oral contraceptives | 3A4 induction | Inducer + substrate | ↓ ethinylestradiol → contraceptive failure; use barrier method |
| Fluoxetine/Paroxetine | Codeine | 2D6 inhibition | Inhibitor blocks prodrug activation | ↓ morphine formation → analgesia failure; consider alternative opioid |
| Omeprazole | Clopidogrel | 2C19 inhibition | Inhibitor blocks prodrug activation | ↓ active thienopyridine → ↑ MACE risk; use pantoprazole (weaker 2C19 inhibitor) |
| Ritonavir | Many 3A4 substrates | 3A4 inhibition (MBI) | Pharmacokinetic booster | Used therapeutically to boost nirmatrelvir (Paxlovid), PI-based HIV regimens |
See also: drug interactions guide · drug transporters (P-gp, OATP1B1)
CYP Enzymes and Pharmacogenomics
CYP2D6 and CYP2C19 are highly polymorphic — their activity varies genetically between individuals. Poor metabolisers (PMs) have no functional enzyme copies; ultrarapid metabolisers (UMs) have duplicated genes. This creates dramatic differences in drug response at standard doses.
CYP2D6
PM frequency5–10% Europeans
UM frequency1–2% Europeans; up to 30% North Africans
PM clinical impactCodeine: no conversion to morphine (analgesia failure); risk of accumulation of parent drug
UM clinical impactCodeine: ultra-rapid conversion to morphine → toxicity at standard doses; black-box warning
CYP2C19
PM frequency2–5% Europeans; 15–20% Asians
UM frequencyRare in most populations
PM clinical impactClopidogrel: poor activation → reduced antiplatelet effect → ↑ MACE risk
UM clinical impactPPIs: reduced effectiveness of omeprazole/lansoprazole at standard doses
Full pharmacogenomics guide: Pharmacogenomics basics ↗ · CPIC guidelines ↗ · PharmGKB ↗
Frequently asked questions
Which CYP enzyme metabolises the most drugs?
CYP3A4 ↗ metabolises approximately 50% of all marketed drugs — it is the most abundant hepatic CYP and is also highly expressed in intestinal enterocytes, contributing to first-pass metabolism. CYP2D6 ↗ handles ~25% of drug metabolism (opioids, antidepressants, beta-blockers) and CYP2C9 ↗ ~15% (NSAIDs, warfarin, sulfonylureas).
What is the difference between CYP inhibition and CYP induction?
Inhibition reduces enzyme activity, increasing substrate plasma concentrations — risk of toxicity. It occurs rapidly (hours). Example: fluconazole (CYP2C9 inhibitor) + warfarin → INR increase. Induction increases enzyme synthesis (via nuclear receptors PXR, CAR), decreasing substrate levels — risk of therapeutic failure. Full induction takes days to weeks. Example: rifampicin (CYP3A4 inducer) + tacrolimus ↗ → subtherapeutic levels. See the drug interactions guide for clinical management.
What happens when two CYP3A4 inhibitors are co-administered?
Two CYP3A4 inhibitors generally produce additive or synergistic enzyme inhibition. Combining ritonavir (a potent mechanism-based CYP3A4 inhibitor, used in pharmacokinetic boosting) with itraconazole (CYP3A4 substrate AND inhibitor) can produce 10-fold or greater increases in co-substrate exposure. This is exploited therapeutically in ritonavir-boosted HIV regimens ↗ and nirmatrelvir/ritonavir (Paxlovid). Check the FDA DDI table ↗ for full inhibition classifications.
Can food affect CYP enzyme activity?
Grapefruit juice contains furanocoumarins (primarily bergamottin) ↗ that irreversibly inactivate intestinal CYP3A4. A single glass can increase simvastatin AUC ~16-fold, increasing myopathy risk. The effect persists 24–72 hours. Clinically important affected drugs include simvastatin, atorvastatin (less so), cyclosporine, tacrolimus, nifedipine, and many others. See the FDA grapefruit interaction guide ↗. St John's Wort is a potent CYP3A4 inducer via PXR activation — it reduces levels of ciclosporin, OCP hormones, and antiretrovirals.
How do FDA and EMA require DDI studies for new drugs?
FDA's 2020 DDI guidance ↗ and ICH M12 (2024) ↗ require in vitro assessment of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 for every new drug. Positive in vitro signals trigger clinical DDI studies. EMA's DDI guideline ↗ similarly requires comprehensive DDI characterisation. PBPK modelling may substitute for clinical studies when validated against clinical data — see our PK basics guide for PBPK background.