Pharmacological interactions of statins

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Abstract

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are effective in reducing the risk of coronary events, and are generally very well tolerated. However, simvastatin, lovastatin, cerivastatin and atorvastatin are biotransformed in the liver primarily by cytochrome P450 (CYP) 3A4, and clinical experience has shown that the risk of adverse effect, such as myopathy, increases with concomitant use of statins with drugs that substantially inhibit CYP 3A4 at therapeutic doses. Indeed, pharmacokinetic interactions (e.g. increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of atorvastatin, cerivastatin, simvastatin or lovastatin and cyclosporine A, mibefradil or nefazodone. In contrast, fluvastatin (mainly metabolized by CYP 2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, an increase in pravastatin bioavailability has been reported in the presence of cyclosporine A, possibly because of an interaction at the level of biliary excretion. In summary, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.

Introduction

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, the so-called statins: atorvastatin, cerivastatin,1 fluvastatin, pravastatin, lovastatin, and simvastatin, can achieve relatively large reductions in plasma cholesterol levels and are a well-established class of drugs for the treatment of hypercholesterolemia [1], [2]. It has been widely demonstrated that cholesterol-lowering therapy with statins reduces cardiovascular events and total mortality rates. Overall, the statins are very selective inhibitors of HMG-CoA reductase and do not show any relevant affinity towards other enzymes or receptor systems [3]. In general, statin monotherapy is well tolerated and has a low frequency of adverse events, as documented by their clinical use for more than 15 years. The most important adverse effects, although rare, associated with statins are myopathy, which can progress to rhabdomyolysis, and asymptomatic increase in hepatic transaminases. The effect on hepatic function for the various HMG-CoA reductase inhibitors is roughly dose-related and 1–3% of patients experience an increase in hepatic enzyme levels [2]. The majority of liver abnormalities occur within the first 3 months of therapy and require monitoring. However, since statins are prescribed on a long-term basis, possible interactions with other drugs deserve attention as many patients will typically receive multiple-drug treatment for concomitant conditions during the course of statin therapy. At the pharmacodynamic level, statins are not prone to interference with other drugs [1]. At the pharmacokinetic level, however, interactions can affect the processes by which statins are absorbed, distributed, metabolized, and excreted. Rhabdomyolysis is an uncommon syndrome and occurs in approximately 0.1% of patients who receive statin in monotherapy [4]. However, the incidence of myopathy or rhabdomyolysis is dose-dependent and is increased when HMG-CoA reductase inhibitors are used in combination with agents that share common metabolic pathways [2]. The issue of safety and drug tolerance is particularly important in primary and secondary prevention of cardiovascular disease, where the risks of long-term therapy, together with the co-prescription of other drugs, must be considered in the context of achievable benefits.

Section snippets

Drug interaction with statins

A drug interaction generally occurs when either the pharmacokinetics or pharmacodynamics of one drug is altered by another [5]. Many drug–drug interactions have been demonstrated in clinical experience with statins and in many respects these interactions are qualitatively and quantitatively comparable for all agents of this class. Some of these interactions are indeed of minor clinical consequence because they neither compromise cholesterol-lowering activity nor increase toxicity. Due to

References (41)

  • J.A. Farmer et al.

    Comparative tolerability of the HMG-CoA reductase inhibitors

    Drug Saf.

    (2000)
  • M. Gibaldi

    Pharmacokinetic variability–drug interactions

    Biopharmaceutics and clinical pharmacokinetics

    (1991)
  • H.E. Bays et al.

    Drug interactions of lipid-altering drugs

    Drug Saf.

    (1998)
  • R.J. Bertz et al.

    Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions

    Clin. Pharmacokinet.

    (1997)
  • N.E. Azie et al.

    The interaction of diltiazem with lovastatin and pravastatin

    Clin. Pharmacol. Ther.

    (1998)
  • O. Mousa et al.

    The interaction of diltiazem with simvastatin

    Clin. Pharmacol. Ther.

    (2000)
  • A.L. Masica et al.

    Intravenous diltiazem and CYP 3A-mediated metabolism

    Br. J. Clin. Pharmacol.

    (2000)
  • K.R. Yeo et al.

    Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients

    Br. J. Clin. Pharmacol.

    (1999)
  • N. Kanathur et al.

    Simvastatin–diltiazem drug interaction resulting in rhabdomyolysis and hepatitis

    Tenn. Med.

    (2001)
  • R. Peces et al.

    Rhabdomyolysis associated with concurrent use of simvastatin and diltiazem

    Nephron

    (2001)
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