Regul Toxicol Pharmacol. Author manuscript; available in PMC 2013 Oct 28.
Published in final edited form as:
Published online 2012 May 3. doi: 10.1016/j.yrtph.2012.04.008
PMCID: PMC3810007
NIHMSID: NIHMS521720
The publisher's final edited version of this article is available at Regul Toxicol Pharmacol
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Abstract
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 1–2 h, 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 0.8–3.1 h 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.
Keywords: (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, Ketone, β-Hydroxybutyrate, Acetoacetate, Kinetics, Safety, Tolerability
1. Introduction
Although
ketosis has generally been portrayed as an unfavorable pathological
state associated with diabetes mellitus and starvation, induction of
mild hyperketonemia may have certain therapeutic benefits (Veech, 2004; Veech et al., 2001).
For example, a high fat, low carbohydrate, protein-restricted ketogenic
diet has been used to treat refractory epilepsy since the early 20th
century (Veech, 2004).
Glucose oxidation serves as the primary energy source for all living
cells; however, under conditions where glucose is limited, such as
during caloric deprivation, the body can utilize fats stored as
triglycerides in adipose tissue as an energy source (Stanfield and Germann, 2008).
During fasting, acetyl-CoA is shunted to the ketogenic pathway in the
mitochondria of the liver, resulting in the production of ketone bodies (i.e., D-β-hydroxybutyrate, acetoacetate, and acetone) (Stanfield and Germann, 2008).
These ketones are transported to extrahepatic tissues, where they can
be converted back to acetyl-CoA and utilized in the citric acid cycle
for energy (Manninen, 2004).
The liver of healthy adults is capable of producing up to 185 g of ketones per day (McPherson and McEneny, 2011).
Ketones account for 2–6% of an individual’s energy needs following an
overnight fast and approximately 40% of energy needs following a 3-day
fast (Laffel, 1999).
There is evidence to suggest that ketones have a higher metabolic
efficiency compared to glucose, providing more energy per unit of oxygen
consumed (Cahill and Veech, 2003; Veech, 2004).
Early studies suggest β-hydroxybutyrate and acetoacetate increased the
motility of sperm, while decreasing oxygen consumption, in contrast to
carbohydrates, lipids and other intermediary metabolites (Veech et al., 2001).
In an isolated rat heart perfusion model, ketones increased
contractility while decreasing oxygen consumption, resulting in 25–28%
increase in hydraulic efficiency (Sato et al., 1995; Kashiwaya et al., 1994).
These observations were attributed to the fact that D-β-hydroxybutyrate
has an inherently greater heat of combustion, releasing approximately
30% more energy per molecule compared to pyruvate (Veech, 2004).
The high metabolic efficiency of ketones has important implications for
the brain, as ketones can be utilized to meet high energy demands,
especially during times of limited glucose availability (Owen, 2005; Owen et al., 1967).
It has been proposed that artificially inducing a mild state of ketosis
will provide additional acetyl-CoA substrates for the citric acid
cycle. This is expected to enhance energy production and thereby improve
physical performance and cognitive function, particularly during states
of fatigue.
Classic ketogenic diets containing high fat,
low carbohydrate and low protein content are difficult to prepare,
unpalatable and may present an atherogenic risk as serum levels of
cholesterol and triglycerides are often elevated (McPherson and McEneny, 2011). Recently, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
(referred to as ketone monoester hereafter) was synthesized as a method
to elevate blood ketone levels without the need to adhere to the strict
ketogenic diet. Following ingestion, the ketone monoester was expected
to undergo complete hydrolysis into its component parts (i.e.,
D-β-hydroxybutyrate and R-1,3-butanediol) by carboxylesterases and
esterases located throughout the gastrointestinal tract, blood, liver
and other tissues (Anders, 1989; Heymann, 1980).
R-1,3-butanediol would then be further metabolized to the ketones,
D-β-hydroxybutyrate and acetoacetate, in the liver by alcohol and
aldehyde dehydrogenase (Desrochers et al., 1995; Tate et al., 1971). Preliminary studies showed the ketone monoester to be hydrolyzed extensively following incubation with human plasma in vitro
(unpublished data). Moreover, in studies conducted in rats, oral
administration of the ketone monoester readily increased blood levels of
D-β-hydroxybutyrate and acetoacetate, whereas the intact ketone
monoester was detected only at very low amounts (unpublished data). As
such, administration of ketone monoester offers a novel approach to
elevate circulating ketone levels.
The
levels of β-hydroxybutyrate and acetoacetate in the blood typically
range from 0.2–0.5 mM, although levels can increase up to 5–7 mM during
periods of limited food intake. Excessively high levels of blood
ketones, such as those observed during diabetic ketoacidosis when blood
levels of ketones may reach 10–20 mM or higher, are considered
pathological. This high level of ketones may overwhelm the body’s
buffering capacity, resulting in metabolic acidosis that may potentially
result in death if left untreated (Cahill and Veech, 2003).
Investigations into the safety profile of the ketone monoester in
humans, at doses intended to provide circulating levels of ketones
similar to those observed during fasting states (i.e.,
approximately 5 mM), are warranted given their potential application in
athletes and persons undergoing strenuous exercise, as examples. An
ascending dose study has been conducted in healthy adults to evaluate
the kinetic parameters of orally administered ketone monoester.
Furthermore, the safety and tolerability of the ketone monoester were
assessed in healthy adults given the ester as part of a meal replacement
beverage for five consecutive days.
