Interactions

Metabolism of statins:

• atorvastatin, cerivastatin and simvastatin is by cytochrome P450 3A4
• also cerivastatin is metabolised via cytochrome P450 2C8
• fluvastatin is metabolised via cytochrome P450 2C9
• pravastatin - metabolised primary via sulphation
• rosuvastatin - the principal isoenzyme involved in rosuvastatin metabolism is cytochrome P450 2C9. Cytochrome P450 3A4 is involved to a lesser extent

Some important drug interactions:

• statins and cytochrome P450 interactions
  • inhibitors of cytochrome P450 3A4 and 2C9 (e.g. macrolide antibiotics, antifungals, cyclosporin, HIV-protease inhibitors) lead to increased statin concentrations
  • barbiturates, carbamazepine, phenytoin and rifampicin lead to reduced statin levels via induction of cytochrome P450 3A4 and 2C9
  • the risk of serious myopathy is also increased when high doses of simvastatin are combined with less potent inhibitors of CYP3A4, including amiodarone, verapamil and diltiazem (1)
  • pharmacokinetic evidence suggests that grapefruit juice should be avoided altogether, as even modest quantities of this drink can significantly increase exposure to simvastatin (1)
  • for atorvastatin, caution should be exercised when combining with any CYP3A4 inhibitor, especially at high doses, and patients should also avoid drinking large quantities of grapefruit juice. Fluvastatin is metabolised by a different cytochrome P450 enzyme (CYP2C9), whilst pravastatin and rosuvastatin. are not substantially metabolised by cytochrome P450 (1)
  • rosuvastatin
    • is thought to have a low propensity for interaction with erythromycin because of the minor role of cytochrome P450 3A4 in metabolism of rosuvastatin (4)
    • in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes (5)
      • rosuvastatin is a poor substrate for these isoenzymes
      • no clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4)
      • concomitant administration of itraconazole (an inhibitor of CYP3A4) and rosuvastatin resulted in a 28% increase in AUC of rosuvastatin. This small increase is not considered clinically significant
      • drug interactions resulting from cytochrome P450-mediated metabolism are not expected
• the effect of warfarin may be enhanced by simvastatin, atorvastatin, rosuvastatin and fluvastatin; pravastatin does not interact with warfarin
• simvastatin and atorvastatin may increase plasma digoxin concentrations
• the risk of myositis with statins may be increased with other lipid-lowering drugs, macrolide antibiotics, and cyclosporin - note that the marketing and distribution of cerivastatin has been suspended in the UK and in all other markets where gemfibrozil is available because of concerns regarding the risk of rhabdomyolysis (6)

The respective summary of product characteristics must be consulted before prescribing a drug mentioned above.

Reference:

1. Current Problems in Pharmacovigilance (2004); 30: 1-12.
2. Drug and Therapeutics Bulletin (2001); 39 (3): 17-21.
3. Prescribers' Journal (1999); 39 (4): 220-21.
4. Baxter K editor. Stockley's Drug Interactions. Statins + macrolides. London: Pharmaceutical Press. Electronic version, 2006. Accessed via http://www.medicinescomplete.com on 11/01/06
5. Summary of Product Characteristics - Crestor. AstraZeneca UK Ltd. Accessed via http://emc.medicines.org.uk on 11/01/06
6. Bayer plc (9th August 2001). Letter re: Lipobay (cerivastatin) - suspension of marketing and distribution.