Caffeine and Methylliberine: A Human Pharmacokinetic Interaction Study Original Research
Main Article Content
Keywords
Caffeine, Methylliberine
Abstract
Introduction: Methylliberine and theacrine are methylurates found in the leaves of various Coffea species and Camellia assamica var. kucha, respectively. We previously demonstrated that the methylxanthine caffeine increased theacrine’s oral bioavailability in humans.
Methods: Consequently, we conducted a double-blind, placebo-controlled pharmacokinetic study in humans administered methylliberine, theacrine, and caffeine to determine methylliberine’s pharmacokinetic interaction potential with either caffeine or theacrine. Subjects received an oral dose of either methylliberine, caffeine, methylliberine plus caffeine, or methylliberine plus theacrine using a randomized, double-blind, crossover design. Blood samples were analyzed using UPLC-MS/MS.
Results: Methylliberine exhibited linear pharmacokinetics that were unaffected by co-administration of either caffeine or theacrine. However, methylliberine co-administration resulted in decreased oral clearance (41.9 ± 19.5 vs. 17.1 ± 7.80 L/hr) and increased half-life (7.2 ± 5.6 versus 15 ± 5.8 hrs) of caffeine. Methylliberine had no impact on caffeine’s maximum concentration (440 ± 140 vs. 458 ± 93.5 ng/mL) or oral volume of distribution (351 ± 148 vs. 316 ± 76.4 L).
Conclusions: We previously demonstrated theacrine bioavailability was enhanced by caffeine, however, caffeine pharmacokinetics were unaffected by theacrine. Herein, we found that methylliberine altered caffeine pharmacokinetics without a reciprocal interaction, which suggests caffeine may interact uniquely with different methylurates.
References
2. Howland J, Rohsenow DJ. Risks of energy drinks mixed with alcohol. JAMA. 2013;309(3):245-246.
3. Kuhman DJ, Joyner KJ, Bloomer RJ. Cognitive Performance and Mood Following Ingestion of a Theacrine-Containing Dietary Supplement, Caffeine, or Placebo by Young Men and Women. Nutrients. 2015;7(11):9618-9632.
4. Wanner H, Pešáková M, Baumann TW, et al. O (2), 1, 9-Trimethyluric acid and 1, 3, 7, 9-tetramethyluric acid in leaves of different Coffea species. Phytochemistry. 1975;14(3):747-750.
5. Zheng XQ, Ye CX, Kato M, Crozier A, Ashihara H. Theacrine (1,3,7,9-tetramethyluric acid) synthesis in leaves of a Chinese tea, kucha (Camellia assamica var. kucha). Phytochemistry. 2002;60(2):129-134.
6. Johnson TB. Purines in the Plant Kingdom: The Discovery of a New Purine in Tea1. Journal of the American Chemical Society. 1937;59(7):1261-1264.
7. Baumann T, Wanner H. The 1, 3, 7, 9-tetramethyluric acid content of cupu (Theobroma grandiflorum Schum.). Acta Amazonica. 1980;10(2):425-425.
8. Petermann JB, Baumann TW. Metabolic Relations between Methylxanthines and Methyluric Acids in Coffea L. Plant Physiol. 1983;73(4):961-964.
9. He H, Ma D, Crone LB, et al. Assessment of the Drug-Drug Interaction Potential Between Theacrine and Caffeine in Humans. J Caffeine Res. 2017;7(3):95-102.
10. Murbach TS, Glavits R, Endres JR, et al. A Toxicological Evaluation of Methylliberine (Dynamine(R)). J Toxicol. 2019;2019:4981420.
11. Bloomer R, Butawan M, Pence J. Acute impact of a single dose of Dynamine®, TeaCrine, caffeine, and their combination on systemic hemodynamics and associated measures in men and women. Medical Research Archives. 2020;8(4).
12. Wang YH, Mondal G, Butawan M, Bloomer RJ, Yates CR. Development of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for characterizing caffeine, methylliberine, and theacrine pharmacokinetics in humans. J Chromatogr B Analyt Technol Biomed Life Sci. 2020;1155:122278.
13. Food and Drug Administration. Guidance for Industry: Drug Interaction Studies —Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. US Department of Health and Human Services (2012). Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf. In.
14. Mitchell DC, Knight CA, Hockenberry J, Teplansky R, Hartman TJ. Beverage caffeine intakes in the U.S. Food and Chemical Toxicology. 2014;63:136-142.
15. Nehlig A. Is caffeine a cognitive enhancer? Journal of Alzheimer's Disease. 2010;20(s1):S85-S94.
16. Nawrot P, Jordan S, Eastwood J, Rotstein J, Hugenholtz A, Feeley M. Effects of caffeine on human health. Food Addit Contam. 2003;20(1):1-30.
17. Spilling the Beans_ How Much Caffeine is Too Much. US Food and Drug Administration https://wwwfdagov/consumers/consumer-updates/spilling-beans-how-much-caffeine-too-much. Accessed Sept. 20, 2019.
18. Petermann J, Baumann TW, Wanner H. A new tetramethyluric acid from Coffea leberica and c. dewevrei. Phytochemistry. 1977;16(5):620-621.
19. Feduccia AA, Wang Y, Simms JA, et al. Locomotor activation by theacrine, a purine alkaloid structurally similar to caffeine: involvement of adenosine and dopamine receptors. Pharmacol Biochem Behav. 2012;102(2):241-248.
20. Benowitz NL. Clinical pharmacology of caffeine. Annu Rev Med. 1990;41:277-288.
21. Taylor L, Mumford P, Roberts M, et al. Safety of TeaCrine®, a non-habituating, naturally-occurring purine alkaloid over eight weeks of continuous use. Journal of the International Society of Sports Nutrition. 2016;13:2.
22. Ziegenfuss TN, Habowski SM, Sandrock JE, Kedia AW, Kerksick CM, Lopez HL. A Two-Part Approach to Examine the Effects of Theacrine (TeaCrine(R)) Supplementation on Oxygen Consumption, Hemodynamic Responses, and Subjective Measures of Cognitive and Psychometric Parameters. Journal of dietary supplements. 2016:1-15.
23. Thorn CF, Aklillu E, McDonagh EM, Klein TE, Altman RB. PharmGKB summary: caffeine pathway. Pharmacogenet Genomics. 2012;22(5):389-395.
24. Arnaud MJ. Pharmacokinetics and metabolism of natural methylxanthines in animal and man. Handbook of experimental pharmacology. 2011(200):33-91.
25. Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clinical Pharmacology & Therapeutics. 1975;18(4):377-390.
26. Yang A, Palmer AA, de Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (Berl). 2010;211(3):245-257.
27. Nehlig A. Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption. Pharmacol Rev. 2018;70(2):384-411.
28. Scott NR, Stambuk D, Chakraborty J, Marks V, Morgan MY. Caffeine clearance and biotransformation in patients with chronic liver disease. Clin Sci (Lond). 1988;74(4):377-384.
29. Desmond PV, Patwardhan RV, Johnson RF, Schenker S. Impaired elimination of caffeine in cirrhosis. Dig Dis Sci. 1980;25(3):193-197.
30. Kalow W, Tang BK. Caffeine as a metabolic probe: exploration of the enzyme-inducing effect of cigarette smoking. Clin Pharmacol Ther. 1991;49(1):44-48.
31. Parsons WD, Neims AH. Effect of smoking on caffeine clearance. Clin Pharmacol Ther. 1978;24(1):40-45.
32. Brown CR, Jacob P, 3rd, Wilson M, Benowitz NL. Changes in rate and pattern of caffeine metabolism after cigarette abstinence. Clin Pharmacol Ther. 1988;43(5):488-491.
33. Perera V, Gross A, McLachlan A. Measurement of CYP1A2 Activity: A Focus on Caffeine as a Probe. Current drug metabolism. 2012;13:667-678.
34. Wang GE, Li YF, Zhai YJ, et al. Theacrine protects against nonalcoholic fatty liver disease by regulating acylcarnitine metabolism. Metabolism. 2018;85:227-239.