Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects
Open accessAbstract
Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1-2h, reaching 3.30 mM and 1.19 mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8-3.1h for β-hydroxybutyrate and 8-14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.
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Clarke et al. (2012) has provided evidence that participants have experienced a range of adverse effects including vomiting, nausea, diarrhea, and abdominal pain.
“Although the side effects of ketone esters are not frequently discussed in the literature, Clarke et al. (2012) has provided evidence that participants have experienced a range of adverse effects including vomiting, nausea, diarrhea, and abdominal pain.”
From Ketone Diester Ingestion Impairs Time-Trial Performance in Professional Cyclists (2017) · cites this paper as Clarke et al., 2012
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- Authors
- Clarke, K., Tchabanenko, K., Pawlosky, R., Carter, E., Todd King, M., Musa-Veloso, K., Ho, M., Roberts, A., Robertson, J., VanItallie, T. B., & Veech, R. L.
- Affiliations
- University of Oxford (GB)
- National Institutes of Health (US)
- Intertek (Canada) (CA)
- St. Luke's-Roosevelt Hospital Center (US)
- Corresponding author
- Clarke, Kieran
- ORCID
- Venue
- Regulatory Toxicology and Pharmacology
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 63
- Issue
- 3
- Pages
- 401-408
- ISSN
- 0273-2300 (ISSN-L)
- PMC
- PMC3810007
- OpenAlex
- W2010511534
- Cited by
- 332
- References
- 29
- Citations by year
- 2026: 22 · 2025: 30 · 2024: 33 · 2023: 31 · 2022: 23 · 2021: 52 · 2020: 29 · 2019: 29 · 2018: 22 · 2017: 14 · 2016: 20 · 2015: 9 · 2014: 14 · 2013: 3 · 2012: 1
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Regulatory Toxicology and Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Oxford
- National Institutes of Health
- Defense Advanced Research Projects Agency
- National Institute on Alcohol Abuse and Alcoholism (ZIDAA000112)
- Topics
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- ketone monoester, hyperketonemia, beta-hydroxybutyrate, acetoacetate, pharmacokinetics, elimination half-life, safety and tolerability, gastrointestinal effects
- MeSH terms
- Adolescent, Adult, Female, Humans, Hydroxybutyrates, Ketones, Kinetics, Male, Middle Aged, Dietary Supplements, Young Adult
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