Oral Bioavailability of Creatine Supplements
Is There Room for Improvement?
Prepared by
Donald W. Miller, Ph.D.
Professor
Department of Pharmacology and Therapeutics
University of Manitoba
Acknowledgements
ISSN & symposium sponsors and organizers
University of Nebraska Medical Center
Dr. Jon Vennerstrom, Dr. Dennis Robinson, Dr. Tom McDonald – University of Manitoba
Nick Miller and Dr. Xiaochen Gu – Vireo Systems
Disclosure
Co-inventor of creatine hydrochloride and other creatine supplement technologies
Member of Scientific Advisory Board for Vireo Systems
Creatine As A Ready Source of High Energy Phosphate
Creatine Sources
To be of benefit, dietary sources of creatine must first be absorbed from the intestine into the bloodstream.
Applications of Creatine Supplements
Athletic performance market- increase power and strength; increase in energy reserve
Muscle recovery- enhanced muscle recovery from injury or workout; reduced soft tissue damage due to intense physical demand
Therapeutic applications
- Muscle wasting diseases – MD, ALS
- Neurological conditions – Alzheimer’s, Parkinson’s, mental retardation, stroke, brain trauma
- Cardiovascular – MI
Concerns with Emerging Indications for Creatine Supplements
Relatively high doses required (5-20 gram/dy)
Inefficient formulations for delivering creatine-side effects including bloating, GI distress, dehydration
Less stringent quality control of product compared to drug or therapeutic agent
Is the standard creatine monohydrate based supplement the best product available for achieving the desired benefits?
General Features of Intestinal Epithelial Cells
Caco-2 Cells as an In Vitro Model for Intestinal Absorption
Immortalized cell line isolated from human colonic carcinoma
Morphological and biochemical properties consistent with intestinal enterocyte (absorptive cell)
Commonly used to assess intestinal absorption of solutes/compounds
Permeability of Creatine Monohydrate Across Caco-2 Monolayers
CRT MONO permeability across intestinal epithelial barrier is relatively low
Journal of Pharmaceutical Sciences vol. 90, page 1593, 2001
Permeability of Creatine Monohydrate Across Caco-2 Monolayers
Mannitol low MW permeability marker used to monitor monolayer integrity
Permeability of 3H-mannitol and 14C-creatine monohydrate is similar in Caco2 monolayers
How can a low permeability agent have complete bioavailability???
Journal of Pharmaceutical Sciences vol. 90, page 1593, 2001
Estimating Oral Bioavailability (%F) Based on In Vitro Indices
Additional Evidence for Incomplete Oral Absorption of CM
Jager et al., J. Intl. Soc. Sports Nutr. 2007
6 subjects given oral dose of CrPyr / Cr C / CrM; 5g molar equivalent
AUC CrPyr = 2985 mM.h
AUC CrM = 2384 mM.h
Significant increase (17%) in bioavailability of CrPyr compared to CrM
Oral Bioavailability of Creatine Supplements: Is There Room for Improvement?
A scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it.
– Max Planck
Factors Influencing Absorption from the GI Tract
Aqueous Solubility – must be in solution to be absorbed
Cell Permeability – measure of how well the compound moves across intestinal barrier
Gastric emptying time
Health / nutritional state of individual
Characteristics of the compound and/or formulation
Can be altered by changing chemistry of the compound
Physiology of the body
Not easily modified
Types of Creatine Supplements
CREATINE SALTS
Creatine monohydrate
Creatine pyruvate
Creatine citrate
Creatine hydrochloride
Creatine ethyl ester
CREATINE PRONUTRIENT
Creatine ethyl ester
Within each category potential for multiple formulations- eg microcrystalline creatine monohydrate; effervescent creatine citrate, etc,etc
Wide variety of available creatine supplements
Aqueous Solubility of Creatine Compounds
NOT ALL CREATINES HAVE THE SAME SOLUBILITY!!!
Summary of Aqueous Solubility Data
Real Lab vs Real-life Solubility
SATURATION SOLUBILITY IN THE LABORATORY
Excess amount of CRT combined with fixed amount of water (RT)
Subject sample to mechanical mixing for 6 hours at room temperature
Take sample, filter, and analyze
REAL LIFE SOLUBILITY
Excess amount of CRT combined with fixed amount of water (cold; 4O C)
Subject sample to manual mixing for 20 seconds
Take sample, filter, and analyze
Real world aqueous solubility of various Creatine Supplements
Importance of Aqueous Solubility of Creatine Supplements
Standard dose of creatine supplements range from 5-30 g per day. How much fluid would it take to solubilize the dose?
CRT MONO
5g Dose 300 ml / 10 fl oz 625 ml |
10g Dose 600 ml / 20 fl oz 1250 ml |
CRT HCL
5g Dose 7 ml / < 0.25 fl oz 10 ml |
10g Dose 14 ml / < 0.5 fl oz 21 ml |
Advantages of CRT HCl Salt Form
Less GI distress
Potential for reduced dose
Potential for more efficient formulations for high dose CRT applications
Comparison of Oral Bioavailability of CRT HCl and CRT Mono
STUDY DESIGN – “BALANCED CROSS-OVER”
10 healthy subjects; each receive CRT Mono and CRT HCl; treatment order was randomly decided; 2 week washout period between treatments
CRT was administered (5 g Dose) with 6 fl. oz. cold water
Blood samples taken at, prior to, and 0.5, 1 and 2 and 3 hours after oral ingestion of creatine
Plasma creatine measured using HPLC
Comparison of plasma Creatine Levels Following Oral Dosing of Creatine Supplement
Comparison of plasma UC for creatine monohydrate and creatine hydrochloride
Oral Bioavailability vs relative bioavailability
FA = AUCoral / AUCiv
RFA = AUCa / AUCb via same administration route
RFA can be used as an index to determine whether improvements in bioavailability actually Occurred between different formulations
Relative Bioavailability of Creatine Hydrochloride Formulation
Relative bioavailability as defined by the FDA:
AUCB X Dose A
AUCA X Dose B
Bioequivalent dosage forms = 1
Relative Bioavailability of CRT HCl compared to CRT Mono
AUCcc X 4.4
AUCcm X 3.9 = 1.7 + 0.1
Key Study Finding
FDA Bioequivalence demonstrates 70% improved plasma uptake with Creatine HCl compared to Creatine Monohydrate
Study Conclusions
Oral bioavailability of many creatine supplements is relatively low
Likely contributor is the low aqueous solubility of CRT relative to doses used
CRT HCl provides substantial improvement in aqueous solubility over other CRT supplements
CRT HCl has improved oral absorption compared to standard CRT mono formulation
Supplementation with CRT HCl provides a more efficient method for enhancing creatine levels in the body
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