title: Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations.
abstract: 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 (Cmax) 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 Cmax of active simvastatin acid fivefold (p < 0.001) and the AUC(0-24) 3.9-fold (p < 0.001). Verapamil increased the Cmax 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.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki, and the Helsinki University Central Hospital, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Kantola
authors.forename: K T
authors.initials: KT
authors.lastname: Kivistö
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000097:blood / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D004917:Erythromycin / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D012016:Reference Values; D019821:Simvastatin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D014700:Verapamil / Q000097:blood / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D004917:Erythromycin; C063287:simvastatin acid; D019821:Simvastatin; D014700:Verapamil; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human