CYP3A4 and CYP3A5: the main drug-metabolising enzymes

CYP3A4 works in the liver and in the lining of the small intestine, so it can reduce the amount of a medicine reaching the bloodstream even before the liver sees it. It deals with a wide range of unrelated medicines, from cholesterol tablets to antibiotics, antifungals, HIV drugs and hormonal contraceptives.

Since many medicines compete for the same enzyme, anything that changes its activity can change the blood level of everything else that relies on it. That is the common thread behind a long list of leaflet warnings, and why a pharmacist asks about all products you take rather than looking at one at a time.

The MHRA's statin guidance names potent CYP3A4 inhibitors that must not be combined with simvastatin: azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, HIV protease inhibitors and others. An updated simvastatin notice also names posaconazole and nefazodone. Blocking the enzyme raises simvastatin blood levels and with them the risk of myopathy, a muscle-damaging side effect, and in rare cases rhabdomyolysis.

For atorvastatin the MHRA advises avoiding the strongest inhibitors where possible and describes dose limits with itraconazole and clarithromycin. The NHS simvastatin page lists the same families of medicines under things that do not mix well with the tablet, along with amlodipine, diltiazem and verapamil.

Grapefruit contains compounds that inhibit CYP3A4 in the gut wall. The NHS says to avoid grapefruit juice with simvastatin because it can stop the medicine working properly, and the MHRA says simvastatin users should avoid it entirely while atorvastatin users should keep intake to very small amounts or avoid it. The NHS carbamazepine page also tells people to avoid grapefruit juice.

The effect is not limited to the hour you drink the juice, so spacing it from the tablet does not reliably help. If you enjoy grapefruit or have been drinking it regularly, ask the pharmacist about your specific medicines rather than assuming all are affected.

Some medicines increase production of CYP3A4. The MHRA's emergency contraception notice lists barbiturates, primidone, phenytoin, carbamazepine, rifampicin, rifabutin, ritonavir, efavirenz, griseofulvin and St John's wort as enzyme inducers, and says the extra enzyme can persist for up to four weeks after stopping.

The MHRA also reported a case in which St John's wort was associated with more frequent and severe seizures in a patient on antiepileptics, and it advised that people with epilepsy should not use products containing it. The practical lesson is that herbal products are not harmless to enzymes and deserve the same checking as prescribed ones.

• Always list herbal and over-the-counter products when you review your medicines.

• Remember that stopping an inducer takes weeks to wear off, so interactions can outlast the product.

• Ask whether a hormonal contraceptive needs back-up if you start an enzyme-inducing medicine.

CYP3A5 shares much of CYP3A4's work, but unlike CYP3A4 its activity differs sharply between individuals, because many people carry versions that produce little or no working enzyme. For most everyday medicines the difference is hidden by CYP3A4, but for a few medicines with narrow safety margins, particularly some used after organ transplantation, blood-level monitoring is used rather than relying on genes.

No UK patient-facing page retrieved for this guide describes CYP3A5 testing, so it is not a routine consumer test, and specialist teams rely on drug-level checks to set doses.

Before starting a new antibiotic, antifungal, HIV medicine, seizure medicine or herbal product, ask a pharmacist to screen it against your existing list. Report muscle pain or weakness on a statin promptly, since it may signal raised levels.

For sudden severe symptoms, such as a seizure, collapse or severe weakness with dark urine, use 999. For other concerns about interactions, NHS 111 or a pharmacist can advise.