Statins and CYP3A4 interactions: clarithromycin, grapefruit and statin choice
Simvastatin and atorvastatin (statins, which lower cholesterol) are cleared by the enzyme CYP3A4, so strong inhibitors of it raise their levels and the risk of rhabdomyolysis (severe muscle breakdown).
Remember
A strong CYP3A4 inhibitor such as clarithromycin raises simvastatin levels and the risk of rhabdomyolysis, whereas rosuvastatin avoids that route and is little affected by clarithromycin.
Statins work by inhibiting HMG-CoA reductase, the enzyme that makes cholesterol. Simvastatin and atorvastatin are CYP3A4 substrates: CYP3A4 is a cytochrome P450 enzyme (one of a family that breaks down many drugs), and it helps to clear them.
Clarithromycin is a macrolide antibiotic and a strong CYP3A4 inhibitor. While the two drugs are taken together, simvastatin is cleared more slowly and its level in the blood rises. Statin muscle toxicity may be dose related, so a higher level makes myalgia (muscle pain) more likely and, more seriously, rhabdomyolysis, which is severe muscle breakdown releasing myoglobin (a muscle protein) into the blood. The kidneys filter myoglobin into the urine, turning it dark, and the kidneys themselves can be injured.
Grapefruit juice inhibits CYP3A4 too, so less simvastatin is cleared and its level in the blood rises. Among the statins, simvastatin has the most important grapefruit interaction, because blocking the enzyme that clears it is like giving a higher dose. With simvastatin the advice is to avoid grapefruit juice, whereas with atorvastatin it is only to avoid large quantities.
Rosuvastatin is high-intensity (it lowers LDL cholesterol by more than 40% at appropriate doses) and is not metabolised (broken down) by CYP3A4, so clarithromycin has little effect on its levels. Pravastatin and fluvastatin are also not metabolised by CYP3A4 to a clinically important extent, but they are usually moderate or lower intensity. Clarithromycin also inhibits the liver uptake transporters OATP1B1 and OATP1B3 (proteins that carry statins from the blood into liver cells), so its effect is not limited to CYP3A4.
Key facts
- CYP3A4 substrates
- simvastatin and atorvastatin are cleared with the help of CYP3A4.
- Strong CYP3A4 inhibitors
- clarithromycin (a macrolide antibiotic) and grapefruit juice are examples, and itraconazole and ketoconazole (antifungals) raise simvastatin levels in the same way.
- Muscle picture
- severe muscle pain with dark urine from myoglobin suggests rhabdomyolysis, and creatine kinase (a muscle enzyme that leaks into the blood when muscle is damaged) is checked.
- Action
- if statin-induced muscle damage is suspected, the statin is stopped and creatine kinase is measured.
- Size of the clarithromycin effect on statin exposure (level in the blood)
- more than five-fold for simvastatin, about two- to four-fold for atorvastatin, about two-fold for pravastatin, and little for fluvastatin and rosuvastatin.
- Clarithromycin and simvastatin
- clarithromycin is contraindicated (must not be used) with simvastatin.
Exam traps
- Inhibition of CYP2C9 does not explain a rise in simvastatin levels, because the enzyme that matters for simvastatin is CYP3A4, whereas CYP2C9 is the route for fluvastatin.
- Induction (making more of the enzyme) of CYP3A4 does not cause statin muscle toxicity, because it speeds up clearance and lowers the level, and clarithromycin is an inhibitor, not an inducer.
- Clarithromycin does not add to the statin's own effect on HMG-CoA reductase, because it is an antibiotic that does not inhibit that enzyme: the interaction is a rise in the simvastatin level.
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