Cited by 264Pharmacogenetics and Drug MetabolismLipoproteins and Cardiovascular HealthDrug Transport and Resistance Mechanisms

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Plasma concentrations of active simvastatin acid are increased by gemfibrozil

Backman, J·2000·Clinical Pharmacology & Therapeutics

DOI 10.1067/mcp.2000.108507

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Abstract

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 1,200 micromol/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-infinity)] by 35% (P < .01) and the AUC(0-infinity) 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.

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Authors: Backman, J.
Affiliations: University of Helsinki (FI)
Corresponding author: Backman, J
ORCID: Backman, J
Venue: Clinical Pharmacology & Therapeutics
Publisher: Wiley
Published: 2000-08
Volume: 68
Issue: 2
Pages: 122-129
ISSN: 0009-9236 (ISSN-L)
DOI: 10.1067/mcp.2000.108507
OpenAlex: W1985258130
Cited by: 264
References: 0
Citations by year: 2026: 4 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 10 · 2018: 2 · 2017: 5 · 2016: 8 · 2015: 15 · 2014: 10 · 2013: 11 · 2012: 12
FWCI: 10.38
Type: journal article
Language: en
Open access: closed
Locations: Clinical Pharmacology & Therapeutics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords: simvastatin, gemfibrozil, simvastatin acid, drug-drug interactions, pharmacokinetics, CYP3A4, myopathy, statins, fibrates, midazolam 1'-hydroxylation, elimination half-life
MeSH terms: Adult, Hypolipidemic Agents, Double-Blind Method, Drug Interactions, Enzyme Inhibitors, Female, Humans, Male, Microsomes, Liver, Gemfibrozil, Cross-Over Studies, Simvastatin

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Plasma concentrations of active simvastatin acid are increased by gemfibrozil

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