Pharmacokinetics and oral absorption of various creatine supplements
| dc.contributor.author | Alraddadi, Eman | |
| dc.contributor.examiningcommittee | Sitar, Daniel (Pharmacology and Therapeutics) | en_US |
| dc.contributor.examiningcommittee | Wang, Jun-Feng (Pharmacology and Therapeutics) | en_US |
| dc.contributor.examiningcommittee | Lakowski, Ted (Pharmacy) | en_US |
| dc.contributor.examiningcommittee | Wasan, Kishor (University of British Columbia) | en_US |
| dc.contributor.supervisor | Miller, Donald (Pharmacology and Therapeutics) | en_US |
| dc.date.accessioned | 2021-11-01T20:31:57Z | |
| dc.date.available | 2021-11-01T20:31:57Z | |
| dc.date.copyright | 2021-10-31 | |
| dc.date.issued | 2021 | en_US |
| dc.date.submitted | 2021-10-31T07:23:00Z | en_US |
| dc.degree.discipline | Pharmacology and Therapeutics | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.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. | en_US |
| dc.description.note | February 2022 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/36093 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Creatine | en_US |
| dc.subject | Pharmacokinetics | en_US |
| dc.subject | Absorption | en_US |
| dc.title | Pharmacokinetics and oral absorption of various creatine supplements | en_US |
| dc.type | doctoral thesis | en_US |