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

Studying the statins

CMAJ 2000;162:1122

In response to: E. Prégent
The metabolism and action of simvastatin (and lovastatin) are complex.1 The parent drug is without intrinsic activity. However, it is readily metabolized to simvastatin acid by nonenzymatic hydrolysis as well as by nonspecific esterases in the liver and other tissues. It is also metabolized through a parallel pathway by hepatic and intestinal CYP3A4. The fact that the CYP3A4 metabolites circulate in blood in much higher concentrations than simvastatin acid has led to speculation that they may account for as much as 75% of the overall HMG­CoA reductase inhibitory activity of the drug. However, simvastatin acid and other open-lactone metabolites are also capable of undergoing reversible lactonization in tissues and exist in an equilibrium between active acid and inactive lactone forms. The lactone forms, including the parent simvastatin, have partition coefficients of around 4.7. In animal experiments, myopathy has been linked to the more lipophilic derivatives.2 Thus, the inactive lactones may be important in the distribution of the drug into tissues, where they are subsequently metabolized and have their effects on cells.

Inhibition of CYP3A4 results in a shift in simvastatin metabolism away from the hydroxylated metabolites toward simvastatin and simvastatin acid. This always produces a more lipid-soluble and more active drug­metabolite profile. The question is, by how much? One can measure the absolute levels of drug and metabolites in blood by quantitative chromatography or by the activity profile of mixed active and inactive drug using a bioassay. I quoted [Education]3 the changes in simvastatin acid induced by itraconazole (19-fold), a potent CYP3A4 inhibitor, from a well-designed placebo-controlled crossover study.4 In Ernest Prégent's opinion, the bioactivity profile (5.2-fold4) would have been more appropriate. One could argue that estimation of bioactive equivalent concentrations may be confounded by high levels of inactive metabolites in the presence of an inhibitor, or that bioactivity does not reflect differences in plasma protein binding or lipophilicity for mixtures of substrates. However, neither the quantitative nor bioassay method tells us unequivocally what is happening in the cell.

In my article I tried to emphasize the characteristics of a drug that may predispose it to a potentially serious drug interaction. Dose-dependent toxicity within or close to the therapeutic range and high first-pass metabolism are clearly associated with HMG­CoA reductase inhibitors. Partly to make a teaching point regarding balanced inhibition and partly because of clinical interest in the drug, I tried to moderate these concerns with atorvastatin. In this case, there is a 1:1 relation between the active parent drug and the active hydroxy metabolites; the metabolites are as potent as or slightly more potent than atorvastatin itself; the differences in lipophilicity are much less than those with simvastatin; and the changes in concentration (a 3.3-fold increase in atorvastatin acid, a 1.6-fold increase in bioactivity) are within the usual dosing ranges for the drug.5 One could not make the same concessions for simvastatin or lovastatin.

The issue regarding the interaction of calcium-channel blockers and statins has been addressed by others.6 There is a major interaction (3.5­6.2 fold elevations in statin concentration) between diltiazem or verapamil and lovastatin or simvastatin.7,8 The change in drug levels is about the same order of magnitude as the interaction of these drugs with erythromycin. Prégent would like us to believe that a recently published meta-analysis9 adequately addresses concerns regarding concomitant use of these drugs with the statins and that their interactions are without clinical significance. However, these data came from studies designed to assess clinical efficacy and not adverse events, least of which would be drug interactions. There were no controls of the number or types of potential inhibitors used by patients (they reported aggregate data for calcium-channel blockers) and the numbers of events were far below those that would be required to show a difference, if any existed. In other words, the data are poor and are vastly underpowered to answer the question.

Robert J. Herman
Department of Medicine and Pharmacology
University of Saskatchewan
Saskatoon, Sask.

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References

  1. Vickers S, Duncan CA, Vyas KP, Kari PH, Arison B, Prakash SR, et al. In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metab Dispos 1990;18:476-82. [MEDLINE]
  2. Pierno S, De Luca A, Tricarico D, Roselli A, Natuzzi F, Ferrannini E, et al. Potential risk of myopathy by HMG-CoA reductase inhibitors: a comparison of pravastatin and simvastatin effects on membrane electrical properties of rat skeletal muscle fibers. J Pharmacol Exp Ther 1995;275:1490-6. [MEDLINE]
  3. Herman RJ. Drug interactions and the statins. CMAJ 1999;161(10):1281-6. [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;63:332-41. [MEDLINE]
  5. Kantola T, Kivistö KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998;64:58-65. [MEDLINE]
  6. Neuvonen PJ, Kantola T, Kivistö KT. Calcium channel blocker-simvastatin interaction. Clin Pharmacol Ther 1999;65:583-5. [MEDLINE]
  7. Kantola T, Kivistö KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998;64:177-82. [MEDLINE]
  8. Azie NE, Brater C, Becker PA, Jones DR, Hall SD. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998;64:369-77. [MEDLINE]
  9. Gruer PJK, 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]

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