Pharmacokinetic Profile of Caffeine and Its Two Main Metabolites in Dried Blood Spots After Five Different Oral Caffeine Administration Forms—A Randomized Crossover Study

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Chiara Tuma Institute of Biochemistry/Center of Preventive Doping Research, German Sport University Cologne, Cologne, Germany
German Research Centre of Elite Sports (momentum), German Sport University Cologne, Cologne, Germany

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Andreas Thomas Institute of Biochemistry/Center of Preventive Doping Research, German Sport University Cologne, Cologne, Germany

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Lasse Trede Institute of Biochemistry/Center of Preventive Doping Research, German Sport University Cologne, Cologne, Germany

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Hans Braun Institute of Biochemistry/Center of Preventive Doping Research, German Sport University Cologne, Cologne, Germany
German Research Centre of Elite Sports (momentum), German Sport University Cologne, Cologne, Germany

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Mario Thevis Institute of Biochemistry/Center of Preventive Doping Research, German Sport University Cologne, Cologne, Germany
European Monitoring Center for Emerging Doping Agents, Cologne/Bonn, Germany

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Caffeine is an ergogenic substance that is consumed globally in many forms. The use of buccally absorbable formulations instead of gastrointestinal uptake has become increasingly popular over the years, especially when accelerated absorption with minimal gastrointestinal stress is desired. This study investigated the impact of five different formulations and administration routes of caffeine on the whole blood concentrations of caffeine, paraxanthine, and theobromine: caffeinated capsules, tablets, shots, pouches, and chewing gums. A uniform dose of caffeine (200 mg) was administered to 16 healthy recreational athletes (26.0 ± 2.1 years) using a randomized crossover design. Samples were taken in the form of dried blood spots at 16 different time points in a 2-hr timeframe after drug administration. The samples were analyzed using a validated liquid chromatography–tandem mass spectrometry method. The results for caffeine showed no significant differences in the overall bioavailability (area under the concentration–time curve), maximal concentration, and time to maximum concentration. However, when analyzing the bioavailability of caffeine in the first 5, 10, and 15 min, the liquid caffeine formulation was superior to other administered forms (p < .05). This indicates that caffeine solubility has a major influence on its absorption rate. In sports, the rate of caffeine absorption must be considered, not only when ingesting anhydrous caffeine, but also when choosing buccal absorption. These findings imply that general guidelines for ergogenic caffeine use should consider the formulation used and, accordingly, the corresponding route of absorption.

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  • Aguilar-Navarro, M., Muñoz, G., Salinero, J., Muñoz-Guerra, J., Fernández-Álvarez, M., Plata, M., & Del Coso, J. (2019). Urine caffeine concentration in doping control samples from 2004 to 2015. Nutrients, 11(2), Article 286.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Amidon, G.L. (2004). Drug bioavailability: Estimation of solubility, permeability, absorption and bioavailability. Edited by H. van de Waterbeemd, H. Lennemas, and P. Artursson. Wiley-VCH, Weinheim, Germany. 2003. xvii + 579 pp. 18 × 24.5 cm. ISBN 3-527-30438-X. $195.00. Journal of Medicinal Chemistry, 47(7), Article 1868.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Arnaud, M. (1993). Metabolism of caffeine and other components of coffee. Caffeine, Coffee and Health, 4395.

  • Arnaud, M.J. (2011). Pharmacokinetics and metabolism of natural methylxanthines in animal and man. In B.B. Fredholm (Ed.), Methylxanthines (pp. 3391). Springer.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Boekema, P.J., Samsom, M., van Berge Henegouwen, G.P., & Smout, A.J. (1999). Coffee and gastrointestinal function: Facts and fiction. A review. Scandinavian Journal of Gastroenterology, 230, 3539.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bonati, M., Latini, R., Galletti, F., Young, J.F., Tognoni, G., & Garattini, S. (1982). Caffeine disposition after oral doses. Clinical Pharmacology and Therapeutics, 32(1), 98106.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Campbell, B., Wilborn, C., La Bounty, P., Taylor, L., Nelson, M.T., Greenwood, M., Ziegenfuss, T.N., Lopez, H.L., Hoffman, J.R., Stout, J.R., Schmitz, S., Collins, R., Kalman, D.S., Antonio, J., & Kreider, R.B. (2013). International Society of Sports Nutrition position stand: Energy drinks. Journal of the International Society of Sports Nutrition, 10(1), 1.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Cox, G.R., Desbrow, B., Montgomery, P.G., Anderson, M.E., Bruce, C.R., Macrides, T.A., Martin, D.T., Moquin, A., Roberts, A., Hawley, J.A., & Burke, L.M. (2002). Effect of different protocols of caffeine intake on metabolism and endurance performance. Journal of Applied Physiology, 93(3), 990999.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • De Kesel, P.M.M., Lambert, W.E., & Stove, C.P. (2015). Does volumetric absorptive microsampling eliminate the hematocrit bias for caffeine and paraxanthine in dried blood samples? A comparative study. Analytica Chimica Acta, 881, 6573.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Del Coso, J., Muñoz, G., & Muñoz-Guerra, J. (2011). Prevalence of caffeine use in elite athletes following its removal from the World Anti-Doping Agency list of banned substances. Applied Physiology, Nutrition, and Metabolism, 36(4), 555561.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Desbrow, B., Barrett, C.M., Minahan, C.L., Grant, G.D., & Leveritt, M.D. (2009). Caffeine, cycling performance, and exogenous CHO oxidation: A dose–response study. Medicine and Science in Sports and Exercise, 41(9), 17441751.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Desbrow, B., Biddulph, C., Devlin, B., Grant, G.D., Anoopkumar-Dukie, S., & Leveritt, M.D. (2012). The effects of different doses of caffeine on endurance cycling time trial performance. Journal of Sports Sciences, 30(2), 115120.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Desbrow, B., & Leveritt, M. (2006). Awareness and use of caffeine by athletes competing at the 2005 Ironman Triathlon World Championships. International Journal of Sport Nutrition and Exercise Metabolism, 16(5), 545558.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Doering, T.M., Fell, J.W., Leveritt, M.D., Desbrow, B., & Shing, C.M. (2014). The effect of a caffeinated mouth-rinse on endurance cycling time-trial performance. International Journal of Sport Nutrition and Exercise Metabolism, 24(1), 9097.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fredholm, B.B. (1995). Adenosine, adenosine receptors and the actions of caffeine. Pharmacology & Toxicology, 76(2), 93101.

  • Gabrielsson, J., & Weiner, D. (2012). Non-compartmental analysis. Methods in Molecular Biology, 929, 377389.

  • Grgic, J., Mikulic, P., Schoenfeld, B.J., Bishop, D.J., & Pedisic, Z. (2019). The influence of caffeine supplementation on resistance exercise: A review. Sports Medicine, 49(1), 1730.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Gu, L., Gonzalez, F.J., Kalow, W., & Tang, B.K. (1992). Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics, 2(2), 7377.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Guest, N.S., VanDusseldorp, T.A., Nelson, M.T., Grgic, J., Schoenfeld, B.J., Jenkins, N.D.M., Arent, S.M., Antonio, J., Stout, J.R., Trexler, E.T., Smith-Ryan, A.E., Goldstein, E.R., Kalman, D.S., & Campbell, B.I. (2021). International society of sports nutrition position stand: Caffeine and exercise performance. Journal of the International Society of Sports Nutrition, 18(1), Article 4.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Guthrie, R., & Susi, A. (1963). A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics, 32, 338343.

    • Search Google Scholar
    • Export Citation
  • Heckman, M.A., Weil, J., & Gonzalez de Mejia, E. (2010). Caffeine (1, 3, 7-trimethylxanthine) in foods: A comprehensive review on consumption, functionality, safety, and regulatory matters. Journal of Food Science, 75(3), R77R87.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Holtzman, S.G., Mante, S., & Minneman, K.P. (1991). Role of adenosine receptors in caffeine tolerance. The Journal of Pharmacology and Experimental Therapeutics, 256(1), 6268.

    • Search Google Scholar
    • Export Citation
  • Kamimori, G.H., Karyekar, C.S., Otterstetter, R., Cox, D.S., Balkin, T.J., Belenky, G.L., & Eddington, N.D. (2002). The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. International Journal of Pharmaceutics, 234(1), 159167.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Laizure, S.C., Meibohm, B., Nelson, K., Chen, F., Hu, Z., & Parker, R.B. (2017). Comparison of caffeine disposition following administration by oral solution (energy drink) and inspired powder (AeroShot) in human subjects. British Journal of Clinical Pharmacology, 83(12), 26872694.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lawson, G., Patel, P., Mulla, H., & Tanna, S. (2012). Dried blood spot sampling with LC-MS analysis for routine therapeutic caffeine monitoring in neonates. ISRN Chromatography, 2012, Article 719.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mamada, H., Iwamoto, K., Nomura, Y., & Uesawa, Y. (2021). Predicting blood-to-plasma concentration ratios of drugs from chemical structures and volumes of distribution in humans. Molecular Diversity, 25(3), 12611270.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Maughan, R.J., Burke, L.M., Dvorak, J., Larson-Meyer, D.E., Peeling, P., Phillips, S.M., Rawson, E.S., Walsh, N.P., Garthe, I., Geyer, H., Meeusen, R., van Loon, L.J.C., Shirreffs, S.M., Spriet, L.L., Stuart, M., Vernec, A., Currell, K., Ali, V.M., Budgett, R.G., ... Engebretsen, L. (2018). IOC consensus statement: Dietary supplements and the high-performance athlete. British Journal of Sports Medicine, 52(7), 439455.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Morris, C., Viriot, S.M., Farooq Mirza, Q.U.A., Morris, G.A., & Lynn, A. (2019). Caffeine release and absorption from caffeinated gums. Food & Function, 10(4), 17921796.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nehlig, A. (2018). Interindividual differences in caffeine metabolism and factors driving caffeine consumption. Pharmacological Reviews, 70(2), 384411.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Page-Sharp, M., Strunk, T., Salman, S., Hibbert, J., Patole, S.K., Manning, L., & Batty, K.T. (2017). Simultaneous determination of pentoxifylline, metabolites M1 (lisofylline), M4 and M5, and caffeine in plasma and dried blood spots for pharmacokinetic studies in preterm infants and neonates. Journal of Pharmaceutical and Biomedical Analysis, 146, 302313.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Patel, P., Mulla, H., Kairamkonda, V., Spooner, N., Gade, S., Della Pasqua, O., Field, D.J., & Pandya, H.C. (2013). Dried blood spots and sparse sampling: A practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants: Caffeine PK in neonates using dried blood spots. British Journal of Clinical Pharmacology, 75(3), 805813.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Peeling, P., Binnie, M.J., Goods, P.S.R., Sim, M., & Burke, L.M. (2018). Evidence-based supplements for the enhancement of athletic performance. International Journal of Sport Nutrition and Exercise Metabolism, 28(2), 178187.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Rasmussen, B.B., Brix, T.H., Kyvik, K.O., & Brøsen, K. (2002). The interindividual differences in the 3-demthylation of caffeine alias CYP1A2 is determined by both genetic and environmental factors. Pharmacogenetics, 12(6), 473478.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ribeiro, J.A., & Sebastião, A.M. (2010). Caffeine and adenosine. Journal of Alzheimer’s Disease, 20(Suppl. 1), S315.

  • Sharma, A., Jaiswal, S., Shukla, M., & Lal, J. (2014). Dried blood spots: Concepts, present status, and future perspectives in bioanalysis. Drug Testing and Analysis, 6(5), 399414.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Skinner, T.L., Jenkins, D.G., Taaffe, D.R., Leveritt, M.D., & Coombes, J.S. (2013). Coinciding exercise with peak serum caffeine does not improve cycling performance. Journal of Science and Medicine in Sport, 16(1), 5459.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Thomas, A., Geyer, H., Guddat, S., Schänzer, W., & Thevis, M. (2011). Dried blood spots (DBS) for doping control analysis. Drug Testing and Analysis, 3(11–12), 806813.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Thomas, A., Geyer, H., Schänzer, W., Crone, C., Kellmann, M., Moehring, T., & Thevis, M. (2012). Sensitive determination of prohibited drugs in dried blood spots (DBS) for doping controls by means of a benchtop quadrupole/Orbitrap mass spectrometer. Analytical and Bioanalytical Chemistry, 403(5), 12791289.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Tretzel, L., Thomas, A., Geyer, H., Pop, V., Schänzer, W., & Thevis, M. (2015). Dried blood spots (DBS) in doping controls: A complementary matrix for improved in- and out-of-competition sports drug testing strategies. Analytical Methods, 7(18), 75967605.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wickham, K.A., & Spriet, L.L. (2018). Administration of caffeine in alternate forms. Sports Medicine, 48(Suppl. 1), 7991.

  • Wilhelm, A.J., den Burger, J.C.G., & Swart, E.L. (2014). Therapeutic drug monitoring by dried blood spot: Progress to date and future directions. Clinical Pharmacokinetics, 53(11), 961973.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wilson, P.B. (2016). Dietary and non-dietary correlates of gastrointestinal distress during the cycle and run of a triathlon. European Journal of Sport Science, 16(4), 448454.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Zailani, N.N.B., & Ho, P.C.L. (2023). Dried blood spots—A platform for therapeutic drug monitoring (TDM) and drug/disease response monitoring (DRM). European Journal of Drug Metabolism and Pharmacokinetics, 48(5), 467494.

    • Crossref
    • Search Google Scholar
    • Export Citation
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