Rhabdomyolysis due to interaction of simvastatin with mibefradil

Schmassmann-Suhijar, Diana; Bullingham, R. E. S.; Gasser, Rodolfo; Schmutz, Jörg; Haefeli, Walter E.

doi:10.1016/s0140-6736(05)78613-x

Cited by 108 publications

(47 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…4 Several cases of statin-associated rhabdomyolysis were reported in patients receiving mibefradil. 39 Both verapamil and diltiazem, which are weak inhibitors of CYP3A4, 28 increase the plasma concentration of simvastatin up to 4-fold, and diltiazem increases the plasma concentration of lovastatin to the same magnitude. 40,41 Cases of rhabdomyolysis have also been reported with the association of diltiazem with atorvastatin or simvastatin, 42,43 suggesting a need for some caution in using these agents simultaneously.…”

Section: Statins and Calcium Antagonistsmentioning

confidence: 99%

Safety of Statins

2004

View full text Add to dashboard Cite

Abstract-Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, however, possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment.

show abstract

Section: Statins and Calcium Antagonistsmentioning

confidence: 99%

Safety of Statins

2004

View full text Add to dashboard Cite

show abstract

“…The CYP3A family, which is the most abundant P450 isoform expressed in both the liver and intestine, is susceptible to reversible and irreversible inhibition because of its broad substrate specificity. Irreversible inhibition, also referred to as mechanism-based inhibition (MBI), causes long-lasting impairment of P450s even after elimination of the inhibitor from blood or tissues, and it may induce serious drug toxicity through increased exposure to coadministered drugs (Rogers and Prpic, 1998;Schmassmann-Suhijar et al, 1998;Zhou et al, 2005). MBI can be characterized as loss of enzyme activity that is dependent on inhibitor concentration and time (Silverman, 1988).…”

mentioning

confidence: 99%

In Vivo Evaluation of Drug-Drug Interaction via Mechanism-Based Inhibition by Macrolide Antibiotics in Cynomolgus Monkeys

Ogasawara¹,

Negishi²,

Kozakai³

et al. 2009

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Irreversible inhibition, characterized as mechanism-based inhibition (MBI), of cytochrome P450 in drugs has to be avoided for their safe use. A comprehensive assessment of drug-drug interaction (DDI) potential is important during the drug discovery process. In the present study, we evaluated the effects of macrolide antibiotics, erythromycin (ERM), clarithromycin (CAM), and azithromycin (AZM), which are mechanism-based inhibitors of CYP3A, on biotransformation of midazolam (MDZ) in monkeys. These macrolides inhibited the formation of 1-hydroxymidazolam in monkey microsomes as functions of incubation time and macrolide concentration. Furthermore, the inactivation potentials of macrolides (k inact / K I : CAM Х ERM > AZM) were as effective as that observed in human samples. In in vivo studies, MDZ was administered orally (1 mg/kg) without or with multiple oral dosing of macrolides (15 mg/kg, twice a day on days 1-3). On day 3, the area under the plasma concentration-time curve (AUC) of MDZ increased 7.0-, 9.9-, and 2.0-fold with ERM, CAM, and AZM, respectively, compared with MDZ alone. Furthermore, the effects of ERM and CAM on the pharmacokinetics of MDZ were also observed on the day (day 4) after completion of macrolide treatments (AUC changes: 7.3-and 7.3-fold, respectively). Because the plasma concentrations of macrolides immediately before MDZ administration on day 4 were much lower than the IC 50 values for reversible CYP3A inhibition, the persistent effects may be predominantly caused by CYP3A inactivation. These results suggest that the monkey might be a suitable animal model to predict DDIs caused by MBI of CYP3A.

show abstract

“…About 200,000 American patients, and double that number worldwide, took the drug (SoRelle, 1998). Soon after its release, a number of case reports showed the dangers of mibefradil drug interactions, including rhabdomyolysis and renal failure with simvastatin (Schmassmann-Suhijar et al, 1998) and symptomatic bradycardia with ␤-blockers (Rogers and Prpic, 1998). Mibefradil is a strong inhibitor of CYP3A4, CYP2D6, and P-glycoprotein (Ernst and Kelly, 1998;Wandel et al, 2000).…”

mentioning

confidence: 99%