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The effect of gemfibrozil on the pharmacokinetics of rosuvastatin

Lookup NU author(s): Dr Colin Brown, Dr Amy Kennedy

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Abstract

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 mumol/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.

Publication metadata

Author(s): Schneck DW, Birmingham BK, Zalikowski JA, Mitchell PD, Wang Y, Martin PD, Lasseter KC, Brown CDA, Windass AS, Raza A

Publication type: Article

Publication status: Published

Journal: Clinical Pharmacology and Therapeutics

Year: 2004

Volume: 75

Issue: 5

Pages: 455-463

ISSN (print): 0009-9236

ISSN (electronic): 1532-6535

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1016/j.clpt.2003.12.014

DOI: 10.1016/j.clpt.2003.12.014

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