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Plasma concentrations of active simvastatin acid are increased by gemfibrozil
Author(s) -
Backman Janne T.,
Kyrklund Carl,
Kivistö Kari T.,
Wang JunSheng,
Neuvonen Pertti J.
Publication year - 2000
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 - 10.1067/mcp.2000.108507
Subject(s) - gemfibrozil , simvastatin , pharmacology , chemistry , pharmacokinetics , cyp3a4 , placebo , medicine , crossover study , endocrinology , cholesterol , metabolism , cytochrome p450 , alternative medicine , pathology
Background Concomitant treatment with simvastatin and gemfibrozil, two lipid‐lowering drugs, has been associated with occurrence of myopathy in case reports. The aim of this study was to determine whether gemfibrozil affects the pharmacokinetics of simvastatin and whether it affects CYP3A4 activity in vitro. Methods A double‐blind, randomized crossover study with two phases (placebo and gemfibrozil) was carried out. Ten healthy volunteers were given gemfibrozil (600 mg twice daily) or placebo orally for 3 days. On day 3 they ingested a single 40‐mg dose of simvastatin. Plasma concentrations of simvastatin and simvastatin acid were measured up to 12 hours. In addition, the effect of gemfibrozil (0 to 1200 μmol/L) on midazolam 1′‐hydroxylation, a CYP3A4 model reaction, was investigated in human liver microsomes in vitro. Results Gemfibrozil increased the mean total area under the plasma concentration–time curve of simvastatin [AUC(0‐∞)] by 35% ( P < .01) and the AUC(0‐∞) of simvastatin acid by 185% ( P < .001). The elimination half‐life of simvastatin was increased by 74% ( P < .05), and that of simvastatin acid was increased by 51% ( P < .01) by gemfibrozil. The peak concentration of simvastatin acid was increased by 112%, from 3.20 ± 2.73 ng/mL to 6.78 ± 4.67 ng/mL (mean ± SD; P < .01). In vitro, gemfibrozil showed no inhibition of midazolam 1′‐hydroxylation. Conclusions Gemfibrozil increases plasma concentrations of simvastatin and, in particular, its active form, simvastatin acid, suggesting that the increased risk of myopathy in combination treatment is, at least partially, of a pharmacokinetic origin. Because gemfibrozil does not inhibit CYP3A4 in vitro, the mechanism of the pharmacokinetic interaction is probably inhibition of non‐CYP3A4–mediated metabolism of simvastatin acid. Clinical Pharmacology & Therapeutics (2000) 68 , 122–129; doi: 10.1067/mcp.2000.108507