Pharmacokinetics and metabolism of natural methylxanthines in animal and man

Arnaud, Maurice J.

doi:10.1007/978-3-642-13443-2_3

Cited by 259Coffee research and impactsPharmacogenetics and Drug MetabolismAlcohol Consumption and Health Effects

Pharmacokinetics and metabolism of natural methylxanthines in animal and man

Arnaud, Maurice J.·2011·Handbook of experimental pharmacology

DOI 10.1007/978-3-642-13443-2_3

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Abstract

Caffeine, theophylline, theobromine, and paraxanthine administered to animals and humans distribute in all body fluids and cross all biological membranes. They do not accumulate in organs or tissues and are extensively metabolized by the liver, with less than 2% of caffeine administered excreted unchanged in human urine. Dose-independent and dose-dependent pharmacokinetics of caffeine and other dimethylxanthines may be observed and explained by saturation of metabolic pathways and impaired elimination due to the immaturity of hepatic enzyme and liver diseases. While gender and menstrual cycle have little effect on their elimination, decreased clearance is seen in women using oral contraceptives and during pregnancy. Obesity, physical exercise, diseases, and particularly smoking and the interactions of drugs affect their elimination owing to either stimulation or inhibition of CYP1A2. Their metabolic pathways exhibit important quantitative and qualitative differences in animal species and man. Chronic ingestion or restriction of caffeine intake in man has a small effect on their disposition, but dietary constituents, including broccoli and herbal tea, as well as alcohol were shown to modify their plasma pharmacokinetics. Using molar ratios of metabolites in plasma and/or urine, phenotyping of various enzyme activities, such as cytochrome monooxygenases, N-acetylation, 8-hydroxylation, and xanthine oxidase, has become a valuable tool to identify polymorphisms and to understand individual variations and potential associations with health risks in epidemiological surveys.

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Absorption of caffeine by the small intestine does not seem to vary by sex, genetic background, environmental factors, or other variables.
“Absorption by the small intestine does not seem to vary by sex, genetic background, environmental factors, or other variables (46), although specific studies are still needed to confirm this premise.”
From The Safety of Ingested Caffeine: A Comprehensive Review (2017) · cites this paper as [46]

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Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption
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The Safety of Ingested Caffeine: A Comprehensive Review
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Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children
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Prevention of Chronic Diseases by Tea: Possible Mechanisms and Human Relevance
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Caffeine Consumption through Coffee: Content in the Beverage, Metabolism, Health Benefits and Risks
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Caffeine and cardiovascular health
Turnbull, D., Rodricks, J. V., Mariano, G. F., & Chowdhury, F. (2017) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2017.07.025 · Cited by 216 · see citing works
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Caffeine as a factor influencing the functioning of the human body-friend or foe?
Rodak, K., Kokot, I., & Kratz, E. M. (2021) · Nutrients · doi:10.3390/nu13093088 · Cited by 188 · see citing works
Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks
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Functional foods as potential therapeutic options for metabolic syndrome
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Occurrence of pharmaceuticals, hormones, and perfluorinated compounds in groundwater in Taiwan
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Studies on prevention of obesity, metabolic syndrome, diabetes, cardiovascular diseases and cancer by tea
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Coffee, caffeine, chlorogenic acid, and the purinergic system.
Stefanello, N., Spanevello, R., Passamonti, S., Porciúncula, L., Bonan, C., Olabiyi, A., da Rocha, J. B. T., Assmann, C., Morsch, V., & Schetinger, M. (2019) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.10.005 · Cited by 108 · see citing works
Bioactive compounds in coffee and their role in lowering the risk of major public health consequences: A review
Urugo, M. M., Tola, Y. B., Ogah, O., & Endale, F. (2023) · Food Science & Nutrition · doi:10.1002/fsn3.3848 · Cited by 114 · see citing works
Novel, Highly Specific N -Demethylases Enable Bacteria To Live on Caffeine and Related Purine Alkaloids
Summers, R. M., Louie, T. M., Yu, C.-L., Gakhar, L., Louie, K., & Subramanian, M. V. (2012) · Journal of Bacteriology · doi:10.1128/jb.06637-11 · Cited by 111 · see citing works
Natural Bioactive Compounds Useful in Clinical Management of Metabolic Syndrome
Noce, A., Lauro, M. D., Daniele, F. D., Zaitseva, A. P., Marrone, G., Borboni, P., & Daniele, N. D. (2021) · Nutrients · doi:10.3390/nu13020630 · Cited by 116 · see citing works
Impact of Coffee and Cacao Purine Metabolites on Neuroplasticity and Neurodegenerative Disease
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Pharmacokinetics of Caffeine: A Systematic Analysis of Reported Data for Application in Metabolic Phenotyping and Liver Function Testing
Grzegorzewski, J., Bartsch, F., Köller, A., & König, M. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.752826 · Cited by 108 · see citing works
“These studies have been reviewed in a broad scope, most recently in (Arnaud, 2011; Nehlig, 2018).”
Background
Health benefits of methylxanthines in neurodegenerative diseases
Oñatibia‐Astibia, A., Franco, R., & Martínez‐Pinilla, E. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201600670 · Cited by 107 · see citing works
Theobromine and the Pharmacology of Cocoa
Smit, H. J. (2010) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-13443-2_7 · Cited by 103 · see citing works
Low, but not high, dose caffeine is a readily available probe for adenosine actions
Fredholm, B. B., Yang, J., & Wang, Y.-Q. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.11.011 · Cited by 99 · see citing works
Pharmacological potential of methylxanthines: Retrospective analysis and future expectations
Monteiro, J., Alves, M. G., Oliveira, P. F., & Silva, B. M. (2018) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2018.1461607 · Cited by 103 · see citing works
Multi-ingredient, Caffeine-containing Dietary Supplements: History, Safety, and Efficacy
Gurley, B. J., Steelman, S. C., & Thomas, S. L. (2014) · Clinical Therapeutics · doi:10.1016/j.clinthera.2014.08.012 · Cited by 96 · see citing works
Bioavailability and metabolism of selected cocoa bioactive compounds: A comprehensive review
Oracz, J., Nebesny, E., Żyżelewicz, D., Budryn, G., & Luzak, B. (2019) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2019.1619160 · Cited by 92 · see citing works
Adenosine and Sleep
Lazarus, M., Chen, J., Huang, Z., Urade, Y., & Fredholm, B. B. (2017) · Handbook of experimental pharmacology · doi:10.1007/164_2017_36 · Cited by 93 · see citing works
Caffeine attenuates metabolic syndrome in diet-induced obese rats
Panchal, S. K., Wong, W.-Y., Kauter, K., Ward, L. C., & Brown, L. (2012) · Nutrition · doi:10.1016/j.nut.2012.02.013 · Cited by 90 · see citing works
Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans
Orrù, M., Guitart, X., Karcz‐Kubicha, M., Solinas, M., Justinová, Z., Barodia, S. K., Zanoveli, J. M., Cortés, A., Lluı́s, C., Casadó, V., et al. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.029 · Cited by 89 · see citing works
Natural products targeting into cancer hallmarks: An update on caffeine, theobromine, and (+)-catechin
Cadoná, F. C., Dantas, R. F., de Mello, G. H., & Silva, F. P. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2021.1913091 · Cited by 88 · see citing works
The buzz on caffeine in invertebrates: Effects on behavior and molecular mechanisms
Mustard, J. A. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1497-8 · Cited by 80 · see citing works
Urine Excretion of Caffeine and Select Caffeine Metabolites Is Common in the US Population and Associated with Caffeine Intake
Rybak, M. E., Sternberg, M., Pao, C., Ahluwalia, N., & Pfeiffer, C. M. (2015) · Journal of Nutrition · doi:10.3945/jn.114.205476 · Cited by 75 · see citing works
Xanthine Alkaloids: Occurrence, Biosynthesis, and Function in Plants
Ashihara, H., Mizuno, K., Yokota, T., & Crozier, A. (2017) · Fortschritte der Chemie Organischer Naturstoffe/Fortschritte der Chemie organischer Naturstoffe/Progress in the chemistry of organic natural products · doi:10.1007/978-3-319-49712-9_1 · Cited by 76 · see citing works
Pharmacokinetics, pharmacodynamics and metabolism of caffeine in newborns
Aranda, J. V., & Beharry, K. D. A. (2020) · Seminars in Fetal and Neonatal Medicine · doi:10.1016/j.siny.2020.101183 · Cited by 72 · see citing works
Alcohol and Caffeine: The Perfect Storm
Ferré, S., & O’Brien, M. C. (2011) · Journal of Caffeine Research · doi:10.1089/jcr.2011.0017 · Cited by 72 · see citing works
Pharmacokinetics of caffeine and its metabolites in plasma and urine after consuming a soluble green/roasted coffee blend by healthy subjects
Martínez-López, S., Sarriá, B., Baeza, G., Mateos, R., & Bravo, L. (2014) · Food Research International · doi:10.1016/j.foodres.2014.05.043 · Cited by 72 · see citing works
Inhibition of Cyclic Nucleotide Phosphodiesterases by Methylxanthines and Related Compounds
Francis, S. H., Sekhar, K. R., Ke, H., & Corbin, J. D. (2010) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-13443-2_4 · Cited by 68 · see citing works
Theobromine, caffeine, and theophylline metabolites in human plasma and urine after consumption of soluble cocoa products with different methylxanthine contents
Martínez‐López, S., Sarriá, B., Gómez‐Juaristi, M., Goya, L., Mateos, R., & Bravo, L. (2014) · Food Research International · doi:10.1016/j.foodres.2014.03.009 · Cited by 68 · see citing works
Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior
Cornelis, M. C., Kacprowski, T., Menni, C., Gustafsson, S., Pivin, E., Adamski, J., Artati, A., Eap, C. B., Ehret, G., Friedrich, N., et al. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw334 · Cited by 175 · see citing works
Pregnancy‐induced changes in the pharmacokinetics of caffeine and its metabolites
Tian, Y., Campbell, S., Stockmann, C. R., Tak, C. R., Schoen, K., Clark, E., Varner, M. W., Spigarelli, M. G., & Sherwin, C. M. T. (2015) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.632 · Cited by 67 · see citing works
Tea and coffee consumption and pathophysiology related to kidney stone formation: a systematic review
Barghouthy, Y., Corrales, M., Doizi, S., Somani, B. K., & Traxer, O. (2020) · World Journal of Urology · doi:10.1007/s00345-020-03466-8 · Cited by 64 · see citing works
Caffeine enhances the antidepressant-like activity of common antidepressant drugs in the forced swim test in mice
Szopa, A., Poleszak, E., Wyska, E., Serefko, A., Wośko, S., Właź, A., Pieróg, M., Wróbel, A., & Właź, P. (2015) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-015-1189-z · Cited by 63 · see citing works
Novel insights on caffeine supplementation, CYP1A2 genotype, physiological responses and exercise performance
Barreto, G., Grecco, B. H., Merola, P., Reis, C. E. G., Gualano, B., & Saunders, B. (2021) · European Journal of Applied Physiology · doi:10.1007/s00421-020-04571-7 · Cited by 64 · see citing works
Insights on the Health Benefits of the Bioactive Compounds of Coffee Silverskin Extract
Fernandez-Gomez, B., Lezama, A., Amigo-Benavent, M., Ullate, M., Herrero, M., Martín, M. Á., Mesa, M. D., & del Castillo, M. D. (2016) · Journal of Functional Foods · doi:10.1016/j.jff.2016.06.001 · Cited by 58 · see citing works
Habitual Coffee and Tea Consumption and Cardiometabolic Biomarkers in the UK Biobank: The Role of Beverage Types and Genetic Variation
Cornelis, M. C., & van Dam, R. M. (2020) · Journal of Nutrition · doi:10.1093/jn/nxaa212 · Cited by 58 · see citing works
Maternal caffeine consumption and small for gestational age births: results from a population-based case-control study
Study, T. N. B. D. P., Hoyt, A. T., Browne, M., Richardson, S., Romitti, P., & Druschel, C. (2014) · Maternal and Child Health Journal · doi:10.1007/s10995-013-1397-4 · Cited by 58 · see citing works
New framework for a non-animal approach adequately assures the safety of cosmetic ingredients – A case study on caffeine
Bury, D., Alexander‐White, C., M.A., H. J. C. I., Cronin, M., Desprez, B., Detroyer, A., Efremenko, A. Y., Firman, J. W., Hack, E., Hewitt, N. J., et al. (2021) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2021.104931 · Cited by 56 · see citing works
Maternal and childhood consumption of coffee, tea and cola beverages in association with childhood leukemia: a meta-analysis
Thomopoulos, T. P., Ntouvelis, E., Diamantaras, A.-A., Tzanoudaki, M., Baka, M., Hatzipantelis, E., Kourti, M., Polychronopoulou, S., Sidi, V., Stiakaki, E., et al. (2015) · Cancer Epidemiology · doi:10.1016/j.canep.2015.08.009 · Cited by 56 · see citing works
Acute caffeine intake increases performance in the 15‐s Wingate test during the menstrual cycle
Lara, B., Gutiérrez‐Hellín, J., Ruíz‐Moreno, C., Romero‐Moraleda, B., & Coso, J. D. (2019) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14175 · Cited by 52 · see citing works
Temporal patterns of caffeine intake in the United States
Martyn, D. M., Lau, A., Richardson, P., & Roberts, A. S. (2017) · Food and Chemical Toxicology · doi:10.1016/j.fct.2017.10.059 · Cited by 51 · see citing works
Caffeine in Kidney Stone Disease: Risk or Benefit?
Peerapen, P., & Thongboonkerd, V. (2018) · Advances in Nutrition · doi:10.1093/advances/nmy016 · Cited by 51 · see citing works
Pretherapeutic uracil and dihydrouracil levels of colorectal cancer patients are associated with sex and toxic side effects during adjuvant 5‐fluorouracil–based chemotherapy
Wettergren, Y., Carlsson, G. U., Odin, E., & Gustavsson, B. G. (2011) · Cancer · doi:10.1002/cncr.26595 · Cited by 48 · see citing works
Theobromine, a Methylxanthine in Cocoa Bean, Stimulates Thermogenesis by Inducing White Fat Browning and Activating Brown Adipocytes
Jang, M. H., Kang, N. H., Mukherjee, S., & Yun, J. W. (2018) · Biotechnology and Bioprocess Engineering · doi:10.1007/s12257-018-0434-y · Cited by 48 · see citing works
Rapid methods to determine procyanidins, anthocyanins, theobromine and caffeine in rat tissues by liquid chromatography-tandem mass spectrometry
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Ergogenic effects of caffeine on peak aerobic cycling power during the menstrual cycle
Lara, B., Gutiérrez‐Hellín, J., Bataller, A. G., Rodríguez-Fernández, P., Romero‐Moraleda, B., & Coso, J. D. (2019) · European Journal of Nutrition · doi:10.1007/s00394-019-02100-7 · Cited by 47 · see citing works
Caffeine: An Overview of Its Beneficial Effects in Experimental Models and Clinical Trials of Parkinson’s Disease
Schepici, G., Silvestro, S., Bramanti, P., & Mazzon, E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134766 · Cited by 47 · see citing works
Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort
Zhao, Y., Lai, Y., Konijnenberg, H., Huerta, J. M., Vinagre‐Aragón, A., Sabin, J., Hansen, J., Petrova, D., Sacerdote, C., Zamora‐Ros, R., et al. (2024) · Neurology · doi:10.1212/wnl.0000000000209201 · Cited by 44 · see citing works
Caffeine for the Pharmacological Treatment of Apnea of Prematurity in the NICU: Dose Selection Conundrum, Therapeutic Drug Monitoring and Genetic Factors
Long, J., Guo, H., He, X., Hu, Y., Xia, Y., Cheng, R., Ding, X., Chen, F., & Xu, J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.681842 · Cited by 44 · see citing works
Neurobehavioral hazard identification and characterization for caffeine
Turnbull, D., Rodricks, J. V., & Mariano, G. (2015) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2015.12.002 · Cited by 45 · see citing works
Caffeine use disorder: An item-response theory analysis of proposed DSM-5 criteria
Ágoston, C., Urbán, R., Richman, M. J., & Demetrovics, Z. (2018) · Addictive Behaviors · doi:10.1016/j.addbeh.2018.02.012 · Cited by 43 · see citing works
Alkaloids and athlete immune function: caffeine, theophylline, gingerol, ephedrine, and their congeners.
Senchina, D. S., Je, H., Kohut, M. L., Na, N., & Ma, P. (2014) · PubMed · Cited by 42 · see citing works
Theobromine alleviates diet-induced obesity in mice via phosphodiesterase-4 inhibition
Jang, M. H., Mukherjee, S., Choi, M. J., Kang, N. H., Pham, H. G., & Yun, J. W. (2020) · European Journal of Nutrition · doi:10.1007/s00394-020-02184-6 · Cited by 42 · see citing works
More Research Is Necessary to Establish the Ergogenic Effect of Caffeine in Female Athletes
Salinero, J. J., Lara, B., Jiménez-Ormeño, E., Romero-Moraleda, B., Giráldez-Costas, V., Baltazar-Martins, G., & Del Coso, J. (2019) · Nutrients · doi:10.3390/nu11071600 · Cited by 38 · see citing works
3-Methylxanthine production through biodegradation of theobromine by Aspergillus sydowii PT-2
Zhou, B., Ma, C., Zheng, C., Xia, T., Ma, B., & Liu, X. (2020) · BMC Microbiology · doi:10.1186/s12866-020-01951-z · Cited by 38 · see citing works
Delineation of the Caffeine C-8 Oxidation Pathway in Pseudomonas sp. Strain CBB1 via Characterization of a New Trimethyluric Acid Monooxygenase and Genes Involved in Trimethyluric Acid Metabolism
Mohanty, S. K., Yu, C.-L., Das, S., Louie, T. M., Gakhar, L., & Subramanian, M. V. (2012) · Journal of Bacteriology · doi:10.1128/jb.00597-12 · Cited by 37 · see citing works
Prenatal caffeine intake differently affects synaptic proteins during fetal brain development
Mioranzza, S., Nunes, F., Marques, D. M., Fioreze, G. T., Rocha, A., Botton, P. H. S., Costa, M. S., & Porciúncula, L. (2014) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2014.04.006 · Cited by 33 · see citing works
Caffeine as a tool to investigate sarcoplasmic reticulum and intracellular calcium dynamics in human skeletal muscles
Reggiani, C. (2020) · Journal of Muscle Research and Cell Motility · doi:10.1007/s10974-020-09574-7 · Cited by 35 · see citing works
Potential Benefits of Coffee Consumption on Improving Biomarkers of Oxidative Stress and Inflammation in Healthy Individuals and Those at Increased Risk of Cardiovascular Disease
Dludla, P. V., Cirilli, I., Marcheggiani, F., Silvestri, S., Orlando, P., Muvhulawa, N., Moetlediwa, M. T., Nkambule, B. B., Mazibuko-Mbeje, S. E., Hlengwa, N., et al. (2023) · Molecules · doi:10.3390/molecules28186440 · Cited by 39 · see citing works
Effect of Caffeine and Other Methylxanthines on Aβ-Homeostasis in SH-SY5Y Cells
Janitschke, D., Nelke, C., Lauer, A. A., Regner-Nelke, L., Winkler, J., Thiel, A., Grimm, H. S., Hartmann, T., & Grimm, M. O. W. (2019) · Biomolecules · doi:10.3390/biom9110689 · Cited by 33 · see citing works
Caffeine for Prevention of Alzheimer’s Disease: Is the A2A Adenosine Receptor Its Target?
Merighi, S., Travagli, A., Nigro, M., Pasquini, S., Cappello, M., Contri, C., Varani, K., Vincenzi, F., Borea, P. A., & Gessi, S. (2023) · Biomolecules · doi:10.3390/biom13060967 · Cited by 34 · see citing works
Protective Effect of Caffeine and Chlorogenic Acids of Coffee in Liver Disease
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Authors: Arnaud, M. J.
Corresponding author: Arnaud, Maurice J.
ORCID: Arnaud, Maurice J.
Venue: Handbook of experimental pharmacology
Publisher: Springer Berlin Heidelberg
Published: 2010-08-19
Issue: 200
Pages: 33-91
ISSN: 0171-2004 (ISSN-L)
1865-0325
DOI: 10.1007/978-3-642-13443-2_3
OpenAlex: W135619738
Cited by: 259
References: 310
Citations by year: 2026: 10 · 2025: 20 · 2024: 26 · 2023: 24 · 2022: 18 · 2021: 21 · 2020: 26 · 2019: 20 · 2018: 13 · 2017: 16 · 2016: 9 · 2015: 12 · 2014: 13 · 2013: 8 · 2012: 13
FWCI: 39.30
Type: book chapter
Language: en
Open access: closed
Locations: Handbook of experimental pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pharmacology › Coffee research and impacts
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Keywords: methylxanthines, caffeine, theophylline, theobromine, paraxanthine, pharmacokinetics, drug metabolism, hepatic metabolism, CYP1A2, enzyme polymorphism, oral contraceptives, pregnancy, smoking, obesity, diet effects, alcohol, xanthine oxidase, N-acetylation, cytochrome P450, species differences, drug interactions
MeSH terms: Animals, Caffeine, Female, Humans, Male, Theobromine, Theophylline, Tissue Distribution, Xanthines, Metabolic Networks and Pathways

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Pharmacokinetics and metabolism of natural methylxanthines in animal and man

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