Cytochrome P450 and Clinically Important Drug Interactions
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Direct answer
Cytochrome P450 is a family of hepatic enzymes that metabolise most drugs, and interactions occur when one drug inhibits or induces the enzyme that clears another. CYP3A4 handles roughly half of clinically used drugs, so its inhibitors raise drug levels and its inducers lower them. Rifampicin is the classic potent inducer, reducing the effect of warfarin and oral contraceptives.
What you must remember
- CYP3A4: metabolises roughly half of clinically used drugs, making it the most important enzyme for interactions.
- Inducers: rifampicin, carbamazepine, phenytoin, phenobarbitone and St John's wort lower levels of co-administered drugs, with induction building over days and fading over weeks.
- Inhibitors: clarithromycin, erythromycin, ketoconazole, itraconazole and ritonavir raise levels of CYP3A4 substrates.
- Grapefruit juice: inhibits intestinal CYP3A4, raising oral levels of some drugs such as felodipine and simvastatin.
- Warfarin: mainly cleared by CYP2C9; metronidazole, fluconazole and amiodarone raise the INR, while rifampicin lowers it.
- Statins: simvastatin and atorvastatin depend on CYP3A4, so clarithromycin raises myopathy risk, and rifampicin lowers atorvastatin exposure.
- Isoniazid: inhibits the metabolism of phenytoin, raising its plasma levels.
Anticipating an interaction during tuberculosis treatment
A 48-year-old woman with a mechanical valve on warfarin needs treatment for tuberculosis, and rifampicin is started. Her INR is likely to fall, so the team must anticipate the interaction rather than react to it.
| Interaction type | Example drugs | Effect on the substrate |
|---|---|---|
| Potent inducer | Rifampicin, carbamazepine, phenytoin | Lowers levels; therapeutic failure |
| Potent inhibitor | Clarithromycin, ketoconazole, ritonavir | Raises levels; toxicity |
| Enzyme-specific inhibitor | Fluconazole (CYP2C9), fluvoxamine (CYP1A2) | Raises levels of specific substrates |
| Food inhibitor | Grapefruit juice (intestinal CYP3A4) | Raises oral levels of some drugs |
| Isoniazid | Phenytoin | Inhibits clearance; raises levels |
The fall in INR is driven by induction, which builds over days, so INR monitoring starts early and warfarin doses are often increased. The reverse happens when rifampicin is stopped, because the induced enzymes return to baseline slowly and the INR can rise again. Until the interaction settles, the INR is checked more often than the routine schedule, in both directions.
Where the exam tries to catch you
Interaction questions turn on which enzyme the drug uses and whether the other drug inhibits or induces it.
- Trap: assuming rifampicin's effect on warfarin is immediate. Correct: induction develops over days and resolves over weeks, so INR must be monitored through the course and after stopping.
- Trap: pairing clarithromycin with simvastatin without a second thought. Correct: CYP3A4 inhibition raises simvastatin exposure and myopathy risk, so the statin is held or changed.
- Trap: ignoring contraceptive failure with enzyme inducers. Correct: rifampicin and other inducers reduce contraceptive hormone levels, so additional contraception is advised.
Frequently asked questions
Which cytochrome P450 enzyme metabolises the most drugs?
CYP3A4 metabolises roughly half of clinically used drugs, making it the most important cytochrome P450 enzyme for interactions. Its potent inhibitors and inducers therefore cause the largest number of clinically significant interactions.
Why does rifampicin reduce the effect of warfarin?
Rifampicin is a potent inducer of several cytochrome P450 enzymes, including those that metabolise warfarin. Induction increases warfarin clearance and lowers the INR, so doses usually need increasing with INR monitoring during and after rifampicin treatment.
Which antibiotic interacts with simvastatin and raises myopathy risk?
Clarithromycin interacts with simvastatin by inhibiting CYP3A4, the enzyme that clears simvastatin, which raises statin levels. The combination increases the risk of myopathy and rhabdomyolysis, so the statin is held or changed during treatment.
Why do enzyme inducers affect oral contraceptives?
Enzyme inducers such as rifampicin increase the metabolism of the oestrogen and progestin components of oral contraceptives, lowering their levels. Reduced hormone exposure can cause contraceptive failure, so additional contraception is advised during treatment.
What is the interaction between isoniazid and phenytoin?
Isoniazid inhibits the hepatic metabolism of phenytoin, raising its plasma levels and risking toxicity. Phenytoin levels should be monitored, and the dose adjusted when isoniazid is started or stopped.