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Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations
Author(s) -
Kantola Teemu,
Kivistö Kari T.,
Neuvonen Pertti J.
Publication year - 1998
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(98)90151-5
Subject(s) - simvastatin , verapamil , cmax , erythromycin , pharmacology , pharmacokinetics , crossover study , chemistry , cyp3a4 , drug interaction , medicine , endocrinology , metabolism , placebo , cytochrome p450 , antibiotics , biochemistry , calcium , alternative medicine , pathology
Objective To study the effects of erythromycin and verapamil on the pharmacokinetics of simvastatin, an inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase. Methods A randomized, double‐blind crossover study was performed with three phases separated by a washout period of 3 weeks. Twelve young, healthy volunteers took orally either 1.5 gm/day erythromycin, 240 mg/day verapamil, or placebo for 2 days. On day 2, 40 mg simvastatin was administered orally. Serum concentrations of simvastatin, simvastatin acid, erythromycin, verapamil, and norverapamil were measured for up to 24 hours. Results Erythromycin and verapamil increased mean peak serum concentration (C max ) of unchanged simvastatin 3.4‐fold ( p < 0.001) and 2.6‐fold ( p < 0.05) and the area under the serum simvastatin concentration‐time curve from time zero to 24 hours [AUC(0–24)] 6.2‐fold ( p < 0.001) and 4.6‐fold ( p < 0.01). Erythromycin increased the mean C max of active simvastatin acid fivefold ( p < 0.001) and the AUC(0–24) 3.9‐fold ( p < 0.001). Verapamil increased the C max of simvastatin acid 3.4‐fold ( p < 0.001) and the AUC(0–24) 2.8‐fold ( p < 0.001). There was more than tenfold interindividual variability in the extent of simvastatin interaction with both erythromycin and verapamil. Conclusions Both erythromycin and verapamil interact considerably with simvastatin, probably by inhibiting its cytochrome P450 (CYP) 3A4‐mediated metabolism. Concomitant administration of erythromycin, verapamil, or other potent inhibitors of CYP3A4 with simvastatin should be avoided. As an alternative, the dosage of simvastatin should be reduced considerably, that is, by about 50% to 80%, at least when a simvastatin dosage higher than 20 mg/day is used. Possible adverse effects, such as elevation of creatine kinase level and muscle tenderness, should be closely monitored when such combinations are used. Clinical Pharmacology & Therapeutics (1998) 64 , 177–182; doi: