Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin
Open accessAbstract
Aims: Simvastatin, a substrate for CYP3A4, is extensively metabolized during the first pass. Our aim was to investigate the effect of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Methods: In a randomized cross‐over study with two phases, 10 healthy volunteers ingested grapefruit juice 200 ml or water (control) for 3 days. On day 3, a single 40‐mg dose of simvastatin was administered with grapefruit juice 200 ml or water. Plasma concentrations of simvastatin and simvastatin acid were determined up to 24 h. Results: Grapefruit juice increased the area under the plasma concentration–time curves from 0 to 24 h [AUC(0–24)] of simvastatin 3.6‐fold (range 1.8–6.0‐fold; P < 0.01) and that of simvastatin acid 3.3‐fold (range 2.1–5.6‐fold; P < 0.01), respectively. The peak concentrations ( C max ) of simvastatin and simvastatin acid were increased 3.9‐fold (range 2.3–9.3‐fold; P < 0.01) and 4.3‐fold (range 2.7–7.9‐fold; P < 0.01) by grapefruit juice. Conclusions: Even one glass of grapefruit juice, taken daily, considerably increases the plasma concentrations of simvastatin and simvastatin acid. Grapefruit juice may increase both the cholesterol‐lowering effect and the risk of adverse effects of simvastatin.
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Only one of the seven identified studies on co-administration of LT4 with foods and beverages in adults was randomized, limiting the ability to draw firm conclusions from the data.
“It should be noted that only one of these is a randomized study (125), thus limiting the ability to draw firm conclusions from the data.”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [125]
The Study design section (page unavailable) confirms that this was a randomized crossover study in adults. But it tested grapefruit juice with simvastatin, not LT4, and it does not establish that only one of seven LT4 food-and-beverage studies was randomized or assess conclusions from those studies. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGrapefruit juice was not found to substantially affect LT4 absorption in a randomized cross-over study of 10 healthy subjects.
“Grapefruit juice, which increases the plasma concentrations of several drugs that are substrates for CYP3A4 and possibly inhibits intestinal uptake transporters, was not found to substantially affect LT4 absorption in a randomized cross-over study of 10 healthy subjects (125).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [125]
The Subjects and Study design sections describe a randomized crossover study of 10 healthy volunteers given grapefruit juice or water. But the drug administered was simvastatin, not LT4; the paper does not assess LT4 absorption (searched: levothyroxine, LT4, thyroxine). (LLM, conf=0.88)
Experimental — accuracy not yet measuredWhen LT4 is co-administered with food, absorption is reduced compared with absorption in the fasting state.
“When LT4 is co-administered with food, absorption is reduced compared with absorption in the fasting state.”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [125]
The Study design and Table 1 passages (page unavailable) compare simvastatin taken with grapefruit juice or water after an overnight fast. Searches for LT4, levothyroxine, and food-versus-fasting absorption found no passage addressing the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measured
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- Authors
- Lilja, J. J., Neuvonen, M., & Neuvonen, P. J.
- Affiliations
- University of Helsinki (FI)
- Corresponding author
- Lilja, Jari J.
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2004-06-04
- Volume
- 58
- Issue
- 1
- Pages
- 56-60
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC1884539
- OpenAlex
- W2081571706
- Cited by
- 157
- References
- 21
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 6 · 2018: 4 · 2017: 4 · 2016: 7 · 2015: 10 · 2014: 6 · 2013: 11 · 2012: 9
- FWCI
- 7.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
- Keywords
- grapefruit juice, simvastatin, simvastatin acid, pharmacokinetics, CYP3A4 inhibition, food-drug interactions, first-pass metabolism, plasma concentration, cholesterol-lowering effect, adverse drug reactions
- MeSH terms
- Adult, Anticholesteremic Agents, Citrus, Humans, Male, Food-Drug Interactions, Cross-Over Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin
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