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The effect of gemfibrozil on the pharmacokinetics of rosuvastatin
Author(s) -
Schneck Dennis W.,
Birmingham Bruce K.,
Zalikowski Julie A.,
Mitchell Patrick D.,
Wang Yi,
Martin Paul D.,
Lasseter Kenneth C.,
Brown Colin D. A.,
Windass Amy S.,
Raza Ali
Publication year - 2004
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/j.clpt.2003.12.014
Subject(s) - rosuvastatin , gemfibrozil , cmax , pharmacokinetics , cerivastatin , pharmacology , rosuvastatin calcium , crossover study , chemistry , placebo , area under the curve , medicine , endocrinology , cholesterol , pravastatin , alternative medicine , pathology
Background Coadministration of statins and gemfibrozil is associated with an increased risk for myopathy, which may be due in part to a pharmacokinetic interaction. Therefore the effect of gemfibrozil on rosuvastatin pharmacokinetics was assessed in healthy volunteers. Rosuvastatin has been shown to be a substrate for the human hepatic uptake transporter organic anion transporter 2 (OATP2). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. The effect of gemfibrozil on rosuvastatin uptake by cells expressing OATP2 was also examined. Methods In a randomized, double‐blind, 2‐period crossover trial, 20 healthy volunteers were given oral doses of gemfibrozil, 600 mg, or placebo twice daily for 7 days. On the fourth morning of each dosing period, a single oral dose of rosuvastatin, 80 mg, was coadministered. Plasma concentrations of rosuvastatin, N ‐desmethyl rosuvastatin, and rosuvastatin‐lactone were measured. In addition, the effect of gemfibrozil on the uptake of radiolabeled rosuvastatin by OATP2‐transfected Xenopus oocytes was studied. Results Gemfibrozil increased the rosuvastatin area under the plasma concentration–time curve from time 0 to the time of the last quantifiable concentration [AUC(0‐t)] 1.88‐fold (90% confidence interval, 1.60–2.21) and the maximum observed rosuvastatin plasma concentration (C max ) 2.21‐fold (90% confidence interval, 1.81–2.69) compared with placebo. N ‐desmethyl rosuvastatin AUC(0‐t) and C max decreased by 48% and 39%, respectively. Pharmacokinetics of rosuvastatin‐lactone was unchanged. The in vitro results indicate that the maximum gemfibrozil inhibition of rosuvastatin OATP2‐mediated uptake was 50%; the inhibition constant for the inhibitory process was 4.0 ± 1.3 μmol/L. Conclusions Gemfibrozil increased rosuvastatin plasma concentrations approximately 2‐fold, which is similar to the effect of gemfibrozil on pravastatin, simvastatin acid, and lovastatin acid plasma concentrations and substantially less than the effect observed for cerivastatin. Gemfibrozil inhibition of OATP2‐mediated rosuvastatin hepatic uptake may contribute to the mechanism of the drug‐drug interaction. Care is warranted when gemfibrozil is coadministered with rosuvastatin and other statins. Clinical Pharmacology & Therapeutics (2004) 75 , 455–463; doi: 10.1016/j.clpt.2003.12.014