Drug-interaction-induced rhabdomyolysis

Segaert, M; Soete, C. De; Vandewiele, Ignace; Verbanck, J.

doi:10.1093/ndt/11.9.1846

Cited by 31 publications

(14 citation statements)

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“…The biotransformation of the pro‐drug simvastatin is similar to that of lovastatin [13] and it might therefore be expected that simvastatin would also interact with itraconazole and other potent CYP3A4 inhibitors to a clinically significant degree. Indeed, several recent case reports indicate that concomitant therapy with simvastatin and itraconazole, cyclosporine or other CYP3A4 inhibitors predisposes to myositis and rhabdomyolysis [17–20]. These case‐reports conform well with our recent data which indicate that simvastatin acid concentrations are greatly increased by itraconazole [21].…”

Section: Discussionsupporting

confidence: 86%

Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin

Kivistö

Kantola

Neuvonen

1998

Brit J Clinical Pharma

158

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AimsThe effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin, two inhibitors of HMG-CoA reductase with different pharmacokinetic properties, were studied. Methods Two separate randomized, placebo-controlled, cross-over studies, each involving 10 healthy volunteers, were carried out. The general design was identical in both studies. The subjects took either 100 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg fluvastatin or 40 mg lovastatin was administered orally. Plasma concentrations of fluvastatin, lovastatin, lovastatin acid, itraconazole and hydroxyitraconazole were determined up to 24 h. Results Itraconazole had no significant effect on the C max (190±124 ng ml Conclusions Itraconazole, even at a small dosage of 100 mg daily, greatly elevated plasma concentrations of lovastatin and its active metabolite, lovastatin acid. Lovastatin should therefore not be used concomitantly with itraconazole and other potent CYP3A4 inhibitors, or the dosage of lovastatin should be greatly reduced while using a CYP3A4 inhibitor. In contrast, fluvastatin concentrations were not significantly increased by itraconazole, indicating that fluvastatin has much less potential than lovastatin for clinically significant interactions with itraconazole and other CYP3A4 inhibitors.Keywords: fluvastatin, interaction, itraconazole, lovastatin, pharmacokinetics inhibitors [5][6][7][8]. The cause of these interactions was at first Introduction unclear, but a recent in vivo study strongly suggests that they result at least partly from inhibition of the Fluvastatin and lovastatin are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the CYP3A4-mediated metabolism of lovastatin [9]. The aim of the present study was to characterize the effect of itraconazole rate-limiting step in cholesterol synthesis, which are widely used in the treatment of hypercholesterolaemia. Lovastatin on the pharmacokinetics of fluvastatin and, in particular, to evaluate the hypothesis that fluvastatin is less liable to is an inactive lactone pro-drug which is hydrolysed in vivo to lovastatin acid, a competitive inhibitor of HMG-CoA interact with CYP3A4 inhibitors such as itraconazole than lovastatin. reductase [1]. However, the oxidative metabolism of lovastatin is primarily mediated by CYP3A4 [2]. The pharmacokinetics of fluvastatin differ considerably from those of lovastatin; fluvastatin is not a pro-drug and it Methods appears to be metabolized mainly by CYP2C9 [3,4].Concomitant use of lovastatin and, for example, cyclosporSubjects ine, erythromycin or itraconazole is associated with a Ten healthy volunteers participated in the fluvastatin study considerably increased risk of skeletal muscle toxicity, a rare (five women and five men; age range, 20-25 years; weight but potentially serious side-effect of HMG-CoA reductase range, 54-85 kg ) and 10 in the lovastatin study (two women and eight men; age range, 19-24 years; weight range,

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Section: Discussionsupporting

confidence: 86%

Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin

Kivistö

Kantola

Neuvonen

1998

Brit J Clinical Pharma

158

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“…Thus, myopathies and even rhabdomyolysis with acute renal failure have been associated with simultaneous use of simvastatin with CYP3A4 inhibitors, e.g. erythromycin [4], diltiazem [5] and itraconazole [6], that increase plasma concentrations of simvastatin and simvastatin acid.…”

Section: Introductionmentioning

confidence: 99%

Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin

Lilja

Neuvonen

2004

Brit J Clinical Pharma

132

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AimsSimvastatin, a substrate for CYP3A4, is extensively metabolized during the first pass. Our aim was to investigate the effect of regular consumption of g rapefruit juice on the pharmacokinetics of simvastatin. MethodsIn a randomized cross-over study with two phases, 10 healthy volunteers ingested grapefruit juice 200 ml or water (control) for 3 days. On day 3, a single 40-mg dose of simvastatin was administered with grapefruit juice 200 ml or water. Plasma concentrations of simvastatin and simvastatin acid were determined up to 24 h. ResultsGrapefruit juice increased the area under the plasma concentration-time curves from 0 to 24 h [AUC(0-24)] of simvastatin 3.6-fold (range 1.8-6.0-fold; P < 0.01) and that of simvastatin acid 3.3-fold (range 2.1-5.6-fold; P < 0.01), respectively. The peak concentrations ( C max ) of simvastatin and simvastatin acid were increased 3.9-fold (range 2.3-9.3-fold; P < 0.01) and 4.3-fold (range 2.7-7.9-fold; P < 0.01) by grapefruit juice. ConclusionsEven one glass of grapefruit juice, taken daily, considerably increases the plasma concentrations of simvastatin and simvastatin acid. Grapefruit juice may increase both the cholesterol-lowering effect and the risk of adverse effects of simvastatin.

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“…[9][10][11] Consequently, the risk with simvastatin and lovastatin is markedly increased by concomitant treatment with CYP3A4-inhibiting drugs, such as itraconazole, cyclosporine (INN, ciclosporin), and mibefradil, which increase the plasma concentrations of these CYP3A4substrate statins. [12][13][14][15][16][17][18] Recently we found that gemfibrozil increases the plasma concentrations of active simvastatin acid, although gemfibrozil is not a CYP3A4 inhibitor. 19 It is Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate Background: Concomitant use of fibrates with statins has been associated with an increased risk of myopathy, but the underlying mechanism of this adverse reaction remains unclear.…”

mentioning

confidence: 99%

Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate

Kyrklund

Backman

Kivistö

et al. 2001

Clin Pharma and Therapeutics

179

106

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Drug-interaction-induced rhabdomyolysis

Cited by 31 publications

References 0 publications

Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin

Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin

Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin

Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate

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