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CMAJ
CMAJ - April 18, 2000JAMC - le 18 avril 2000

Studying the statins

CMAJ 2000;162:1124

In response to: E. Prégent
We thank Ernest Prégent for his comments about our editorial.1 He is correct to point out that not all reports of significant rates of myalgia in patients receiving combination therapy with a statin and certain other agents have involved simvastatin or lovastatin. However, the reports with these particular HMG­CoA reductase inhibitors are often based mechanistically on their inhibition by a CYP3A4 inhibitor. The concept of differential susceptibility of the statins in terms of CYP3A4 inhibition still holds true.

The myopathy reported in patients receiving combination therapy with pravastatin and cyclosporine clearly is not based on inhibition of CYP3A4 metabolism. We all continue to learn as these drugs are used, and therefore interactions are often not recognized until years after clinical trials are completed. Adverse reports of large trials such as those discussed by Gruer and colleagues2 are reassuring. However, the data do have limitations. This study was conducted when our understanding of cytochrome-mediated drug metabolism was in the early stages. Therefore, drug interactions may have been under-recognized. While the mechanism of cyclosporine­pravastatin interactions is not known, it could relate to interference with transport mediated by P-glycoprotein.3

We know that a few drugs, such as niacin, fibrates and cyclosporine, increase the likelihood of myopathy with some, not all statins as Prégent states. In the end, we all agree that the potential for myopathy increases when the most potent CYP3A4 inhibitors are given with statins metabolized by CYP3A4.

Lori E. Shapiro
Neil H. Shear
Program in Clinical Pharmacology
Sunnybrook & Women's College
Health Sciences Centre
Toronto, Ont.

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References

  1. Shapiro LE, Shear NH. Drug­drug interactions: How scared should we be? [editorial]. CMAJ 1999;161(10):1266-7. [MEDLINE]
  2. Gruer PJ, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol 1999;84:811-5. [MEDLINE]
  3. Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 1999;16:408-14. [MEDLINE]

© 2000 Canadian Medical Association or its licensors