Pharmacokinetics and oral absorption of various creatine supplements
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Date
2021
Authors
Alraddadi, Eman
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Abstract
Creatine is a dietary supplement with an extensive history of use in athletes
and more recently in various neurological and muscular pathologies. For both
indications, large doses (>30 g/day) of creatine monohydrate (CM) are required for
beneficial effects to manifest. Based on the doses required and the
physicochemical characteristics of creatine, oral absorption of CM is likely
incomplete. The research objectives of this dissertation were to determine the
absolute oral bioavailability and pharmacokinetic (PK) profile of CM and to
identify through in-silico simulations, alternative dosing strategies and
formulations resulting in improved oral bioavailability and/or tissue distribution.
The absolute oral bioavailability of CM was determined in rats at two different
doses (10 mg/kg and 70 mg/kg) and found to be 53% and 16% for low and high
dose CM, respectively. Using GastroplusTM software, a physiology-based PK
(PBPK) model for CM was constructed and compared to the PK data obtained in
rats. With good agreement between the simulated and observed data in rats, the
model was then scaled-up to compare creatine plasma and tissue levels following
various dosing strategies (i.e. once daily vs. 4 times daily, and sustained release
(SR) vs. immediate release (IR)) in humans. While the model suggested that SRCM
resulted in comparable plasma area under the curve (AUCss) with IR-CM, the
tissue levels were predicted to be significantly higher following SR-CM (41.3 %
and 18.3% increase in brain and muscle concentrations, respectively). The model
was also used to predict the impact of other creatine salt forms. For these
simulations, CM was compared to creatine hydrochloide (CHCl), creatine citrate
(CrC) and creatine pyruvate (CrPyr). Following administration of a large dose (20
g/day), AUC0-∞ in plasma increased by 24.4, 52.1, and 56.3% for CrC, CrPyr, and
CHCL, respectively. In the brain, AUC0-∞ increased by 31.0, 55.1, and 70.1%, and
in the muscles by 20.1, 35.1, and 40.1%, for CrC, CrPyr, and CHCl, respectively.
Our results suggest that the oral bioavailability of CM is less than complete and is
dose-dependent. These studies suggest that newer forms and dosage formulations
of creatine will result in superior accumulation of creatine in the tissues.
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Keywords
Creatine, Pharmacokinetics, Absorption