LETTER TO THE EDITOR
Possible risks to patients receiving statins combined with other medications
Philip D. Hansten, PharmD
School of Pharmacy, University of Washington, Seattle, Washington 98195-7630, USA
hansten{at}u.washington.edu
The American College of Cardiology/American Heart Association/National Heart Lung, and Blood Institute (ACC/AHA/NHLBI) Clinical Advisory on Statins (1) was a timely review of an important issue, but I believe that additional information on the issue of drug interactions would be helpful to clinicians who manage patients receiving statins with other medications.
First, as for combining statins with CYP3A4 inhibitors, only lovastatin and simvastatin undergo extensive (90% or more) presystemic metabolism by CYP3A4 in the gut wall and liver (2). Hence, the risk of statin-induced myopathy due to CYP3A4 inhibitors appears to be considerably greater for lovastatin and simvastatin compared to the other statins. For example, potent CYP3A4 inhibitors such as itraconazole can produce 10- to 20-fold increases in the serum concentrations of lovastatin or simvastatin (3,4). Atorvastatin is also metabolized by CYP3A4, but it does not undergo as extensive presystemic metabolism as lovastatin and simvastatin. Accordingly, potent CYP3A4 inhibitors tend to produce two- to four-fold increases in atorvastatin serum concentrations (5,6). Pravastatin is not metabolized by CYP3A4 or other cytochrome P450 isozymes, and inhibition of CYP3A4 has little effect on its pharmacokinetics (4,6). Fluvastatin is metabolized primarily by CYP2C9 and also is unlikely to interact with CYP3A4 inhibitors (2).
Second, as for macrolides and statins, erythromycin and clarithromycin are correctly listed as potentially increasing the risk of statin-associated myopathy. As described above, this caution results from the ability of these two macrolide antibiotics to inhibit the CYP3A4 metabolism of lovastatin, simvastatin, and to a lesser extent atorvastatin (7,8). But a separate bullet point lists "Macrolide antibiotics" (page 571 under "Prevention" heading). This might lead some readers to conclude that azithromycin and dirithromycin interact with statins, but substantial evidence suggests that these macrolides do not inhibit CYP3A4 (9).
Finally, as for the interaction of calcium-channel blockers and statins, verapamil—a known CYP3A4 inhibitor—is listed as increasing the risk of statin-associated myopathy, but diltiazem is not mentioned. Available evidence suggests that verapamil and diltiazem are roughly equivalent (moderate) inhibitors of CYP3A4. Indeed, diltiazem has been shown in pharmacokinetic studies to increase serum concentrations of both lovastatin and simvastatin (10,11), and isolated cases of myopathy have been reported in patients receiving simvastatin plus diltiazem (12,13). The available evidence would thus suggest that the risk of adding verapamil or diltiazem to simvastatin or lovastatin is roughly equivalent. Conversely, calcium-channel blockers such as amlodipine, felodipine, and nifedipine have not been shown to inhibit CYP3A4 significantly.
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References
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1. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:567–572[Free Full Text]
2. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 2002;41:343–370[CrossRef][Medline]
3. Neuvonen PJ, Jalava KM. Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther. 1996;60:54–61[CrossRef][Medline]
4. Neuvonen PJ, Kantola T, Kivistö KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther. 1998;63:332–341[CrossRef][Medline]
5. Kantola T, Kivistö KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther. 1998;64:58–65[CrossRef][Medline]
6. Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P. Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clin Pharmacol Ther. 2000;68:391–400[CrossRef][Medline]
7. Kantola T, Kivistö KT, Neuvonen P. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 1998;64:177–182[CrossRef][Medline]
8. Lee AJ, Maddix DS. Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Ann Pharmacother. 2001;35:26–31[Abstract]
9. Watkins VS, Polk RE, Stotka JL. Drug interactions of macrolides: emphasis on dirithromycin. Ann Pharmacother. 1997;31:349–356[Abstract]
10. Azie NE, Brater C, Becker PA, Jones DR, Hall SD. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther. 1998;64:369–377[CrossRef][Medline]
11. Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther. 2000;67:267–274[CrossRef][Medline]
12. Peces R, Pobes A. Rhabdomyolysis associated with concurrent use of simvastatin and diltiazem. Nephron. 2001;89:117–118[CrossRef][Medline]
13. Kanathur N, Mathai MG, Byrd RP Jr, Fields CL, Roy TM. Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and hepatitis. Tenn Med. 2001;94:339–341[Medline]
This article has been cited by other articles:
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C. D. Williams
Clinical decision making on statin drug interactions
J. Am. Coll. Cardiol.,
July 16, 2003;
42(2):
396 - 397.
[Full Text]
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