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

Plasma concentrations of active simvastatin acid are increased by gemfibrozil

Backman, J·2000·Clinical Pharmacology & Therapeutics

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.

Integrity signals

Registry

Crossref · 10.1067/mcp.2000.108507

Cites

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Still being checked.

Cited by

Sorted by citations

Authors
Backman, J.
Affiliations
University of Helsinki (FI)
Corresponding author
Backman, J
Venue
Clinical Pharmacology & Therapeutics
Publisher
Wiley
Published
2000-08
Volume
68
Issue
2
Pages
122-129
ISSN
0009-9236 (ISSN-L)
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 › Surgery › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review