Gemfibrozil greatly increases plasma concentrations of cerivastatin

Clinical Pharmacology & TherapeuticsVolume 72, Issue 6 p. 685-691 Pharmacokinetics and Drug Disposition Gemfibrozil greatly increases plasma concentrations of cerivastatin Janne T. Backman MD, Janne T. Backman MD Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central HospitalSearch for more papers by this authorCarl Kyrklund MB, Carl Kyrklund MB Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central HospitalSearch for more papers by this authorMikko Neuvonen MSc, Mikko Neuvonen MSc Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central HospitalSearch for more papers by this authorPertti J. Neuvonen MD, Pertti J. Neuvonen MD Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central HospitalSearch for more papers by this author Janne T. Backman MD, Janne T. Backman MD Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central HospitalSearch for more papers by this authorCarl Kyrklund MB, Carl Kyrklund MB Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central HospitalSearch for more papers by this authorMikko Neuvonen MSc, Mikko Neuvonen MSc Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central HospitalSearch for more papers by this authorPertti J. Neuvonen MD, Pertti J. Neuvonen MD Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central HospitalSearch for more papers by this author First published: 28 December 2002 https://doi.org/10.1067/mcp.2002.128469Citations: 71 Pertti J. Neuvonen, MD, Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, FIN-00290, Helsinki, Finland. E-mail: [email protected] AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Background Concomitant use of gemfibrozil with statins, particularly with cerivastatin, increases the risk of rhabdomyolysis, but the mechanism of this potentially fatal drug interaction remains unclear. Our aim was to study the effect of gemfibrozil on cerivastatin pharmacokinetics. Methods In a randomized, double-blind crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo twice daily for 3 days. On day 3, each subject ingested a single 0.3-mg dose of cerivastatin. Plasma concentrations of cerivastatin, its metabolites, and gemfibrozil were measured up to 24 hours. Results During gemfibrozil treatment, the area under the plasma concentration-time curve [AUC(0-∞)] of parent cerivastatin was on average 559% (range, 138% to 995%; P = .0002) and the peak concentration in plasma was 307% (138% to 809%; P = .0019) of the corresponding values in the placebo phase. Gemfibrozil increased the AUC(0-∞) of cerivastatin lactone, on average, to 440% (94% to 594%; P = .0024) and that of metabolite M-1 to 435% (216% to 802%; P = .0002) of the control (placebo) values, whereas the AUC(0–24) of metabolite M-23 was decreased to 22% (11% to 74%; P = .0017). Conclusions Gemfibrozil greatly increases plasma concentrations of cerivastatin, cerivastatin lactone, and metabolite M-1, whereas the level of metabolite M-23 is markedly reduced by gemfibrozil. Gemfibrozil therefore inhibits the formation of M-23, which is thought to be dependent on CYP2C8. The increased exposure to cerivastatin in the presence of gemfibrozil may explain the high incidence of myopathy observed with this combination, although the role of pharmacodynamic interactions between these 2 agents cannot be excluded. Clinical Pharmacology & Therapeutics (2002) 72, 685–691; doi: 10.1067/mcp.2002.128469 Citing Literature Volume72, Issue6December 2002Pages 685-691 RelatedInformation