Studying the statins
CMAJ 2000;162:1122
See responses from: R.J.Herman; L.E. Shapiro, N.H. Shear
There are several inaccuracies in Robert Herman's review of the statins [Education].1 First, he listed several inhibitors of cytochrome P-450 (CYP), including diltiazem and substances found in grapefruit juice and green tea, and labelled them all "potent inhibitors." Calcium-channel blockers have not been associated with an increase in myopathy in either controlled clinical trials or clinical practice.2 Grapefruit juice, when taken in normal quantities in the morning, has minimal effects on the serum concentration of HMGCoA reductase inhibitors following administration of lovastatin and has not been shown to have any clinically significant adverse effects.3
Second, Herman singled out lovastatin and simvastatin as being particularly likely to cause drug interactions by implying that active metabolites play no significant role. He noted that atorvastatin and cerivastatin are at least partially exonerated because "active ... metabolites of atorvastatin and cerivastatin contribute in large measure to their overall clinical activity." He concluded, "Thus, inhibition of first-pass metabolism of lovastatin and simvastatin could result in 1020 fold elevations (oral availability increasing from 5% to 100%) in steady-state concentrations with a marked liability to drug toxicity." This is also inaccurate. Approximately 75% of the HMG-CoA reductase inhibitory activity of simvastatin results from 3 active metabolites. Therefore, measuring only the parent compound, such as simvastatin, grossly overestimates the overall interaction with CYP inhibitors.2
Editorialists Lori Shapiro and Neil Shear highlighted the statins as an example of a drug class in which not all members share similar drug interactions [Editorial].4 They stated, "To date, all reports of significantly increased rates of myalgia in patients receiving combination therapy with a statin and certain other agents involve simvastatin or lovastatin, the statins with the highest known metabolic dependency on the CYP3A4 pathway for elimination." This is simply not true; several cases of myopathy have been reported in patients taking pravastatin concomitantly with cyclosporine.2 In addition, a significant increase in creatine kinase was documented in a patient taking nefazodone and pravastatin concomitantly, necessitating the discontinuation of nefazodone.5
Simvastatin has been well tolerated by millions of patients and has been shown to decrease coronary mortality by 42% in patients with high cholesterol levels and heart disease. Some drugs, such as niacin, fibrates and cyclosporine, increase the likelihood of myopathy with all statins. Other drugs, such as erythromycin, clarithromycin, the azole antifungals, nefazodone and other HIV protease inhibitors, increase the potential for myopathy when given concomitantly with statins metabolized by CYP3A4.
Ernest Prégent
Emergency medicine specialist
Director of medical services
Merck Frosst Canada & Co.
Pointe-Claire, Que.
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References
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Herman RJ. Drug interactions and the statins. CMAJ 1999;161(10):1281-6. [MEDLINE]
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]
Rogers JD, Zhao J, Liu L, Amin RD, Gagliano KD, Porras AG, et al. Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Clin Pharmacol Ther 1999;66:358-66. [MEDLINE]
Shapiro LE, Shear NH. Drugdrug interactions: How scared should we be? [editorial]. CMAJ 1999;161(10):1266-7. [MEDLINE]
Alderman CP. Possible interaction between nefazodone and pravastatin [letter]. Ann Pharmacother 1999;33:871. [MEDLINE]
© 2000 Canadian Medical Association or its licensors
