The DOI matches its Crossref record; 311 of the 311 references it cites were found in a registry or an index.
Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man
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 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]
Citations
Cites
Miletzki, B., & Gleiter, C. H. (2005) · Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz · doi:10.1007/s00103-005-1024-7 · Cited by 9,401
Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., & Guengerich, F. P. (1994) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)22379-5 · Cited by 2,785 · cited 1×
“2% of total CYP (Shimada et al. 1994), is responsible for more than 90% of caffeine clearance.”
BackgroundRosal, R., Rodríguez, A. R., Perdigón-Melón, J. A., Petre, A. L., García‐Calvo, E., Gómez, M. J., Agüera, A., & Fernández‐Alba, A. R. (2009) · Water Research · doi:10.1016/j.watres.2009.07.004 · Cited by 1,015
Drug Interactions with Tobacco Smoking
Zevin, S., & Benowitz, N. L. (1999) · Clinical Pharmacokinetics · doi:10.2165/00003088-199936060-00004 · Cited by 711
Encyclopaedia of food science, food technology, and nutrition
(1993) · Choice Reviews Online · doi:10.5860/choice.31-1853 · Cited by 515
Clinical Pharmacokinetics of Theophylline
OGILVIE, R. I. (1978) · Clinical Pharmacokinetics · doi:10.2165/00003088-197803040-00002 · Cited by 448
Butler, M. A., Lang, N. P., Young, J. F., Caporaso, N. E., Vineis, P., Hayes, R. B., Teitel, C. H., Massengill, J., Lawsen, M. F., & Kadlubar, F. F. (1992) · Pharmacogenetics · doi:10.1097/00008571-199206000-00003 · Cited by 419
The absolute bioavailability of caffeine in man
Blanchard, J., & Sawers, S. J. A. (1983) · European Journal of Clinical Pharmacology · doi:10.1007/bf00613933 · Cited by 378
Fluvoxamine is a potent inhibitor of cytochrome P4501A2
Brøsen, K., Skjelbo, E., Rasmussen, B. B., Poulsen, H. E., & Loft, S. H. (1993) · Biochemical Pharmacology · doi:10.1016/0006-2952(93)90272-x · Cited by 374
Caffeine disposition after oral doses
Bonati, M., Latini, R., Galletti, F., Young, J. F., Tognoni, G., & Garattini, S. (1982) · Clinical Pharmacology and Therapeutics · doi:10.1038/clpt.1982.132 · Cited by 353
Research works printed but not linked: 16
- Arnaud MJ (1980) Metabolism of labeled paraxanthine in the rat: comparison of rat and human metabolic pathway. Nutr Rev 38(5):196–200
- Arnaud MJ (1983) The effect of dietary factors on the bioavailability of methylxanthines. Proceedings of the toxicology forum, Aspen, Colorado, pp 234–243
- Arnaud MJ (1988) The metabolism of coffee constituents in coffee, vol 3. In: Clarke RJ, Macrae R (eds) Physiology. Elsevier, London, pp 33–55
- Arnaud MJ (1998) Pharmacokinetics and metabolism of caffeine. In: Snel J, Lorist MM (eds) Nicotine, caffeine and social drink, behaviour and brain function. Harwood, Amsterdam, pp 153–165
- Arnaud MJ, Bracco I (1981) Distribution and metabolism of theophylline in the pregnant rat: presence of a blood brain barrier. Experientia 37(6):665
- Arnaud MJ, Enslen M (1992) The role of paraxanthine in mediating physiological effects of caffeine. In: 14th international conference in coffee science, San Francisco, 14–19 July 1991. Proceedings ASIC, Paris, pp 71–79
- Arnaud MJ, Gétaz F (1982) Postnatal establishment of a blood-brain barrier for theobromine in the rat. Experientia 38(6):752
- Arnaud MJ, Gétaz F (1983) Theobromine distribution in the pregnant rat and the fetus and the impairment of its metabolism due to pregnancy. Experientia 39(6):678
- Arnaud MJ, Richli U, Philippossian G (1986b) Isolation and identification of paraxanthine glucuronide as the major caffeine metabolite in mice. Experientia 42(6):696
- Arnaud MJ, Welsch C (1979b) Metabolism of [1-Me-14C] paraxanthine in the rat: identification of a new metabolite. Experientia 35(7):946
- Arnaud MJ, Welsch C (1980a) Caffeine metabolism in human subjects. In: Proceedings of the ninth international colloquium on science and technology of coffee. Association Scientifique Internationale du Cafe, London, pp 385–395
- Arnaud MJ, Welsch C (1980b) Quantitative analysis of theophylline metabolites by HPLC, after oral or i.v. administration. Experientia 36(6):704
- Arnaud MJ, Wietholtz H, Voegelin M, Bircher J, Preisig R (1982b) Assessment of the cytochrome P-448 dependent liver enzyme system by a caffeine breath test. In: Sato R (ed) Microsomes drug oxidation and drug toxicity. Wiley, New York, pp 443–444
- Levy M, Granit L, Zylber-Katz E (1984) Chronopharmacokinetics of caffeine in healthy volunteers. Annu Rev Chronopharmacol 1:97–100
- Morisot C, Simoens C, Trublin F, Lhermitte M, Gremillet C, Robert MH, Lequin P (1990) Efficacité de la caffeine transcutanée dans le traitement des apnées du prématuré. Arch Fr Pediatr 47(3):221–224
- Schrenk D (1998) Impact of dioxin-type induction of drug-metabolizing enzymes on the metabolism of endo- and xenobiotics. Biochem Pharmacol 5(8):1155–1162
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Sorted by citations
Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption
Nehlig, A. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014407 · Cited by 632
The Safety of Ingested Caffeine: A Comprehensive Review
Temple, J. L., Bernard, C., Lipshultz, S. E., Czachor, J. D., Westphal, J. A., & Mestre, M. A. (2017) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2017.00080 · Cited by 557
Coffee: Biochemistry and Potential Impact on Health
Ludwig, I. A., Clifford, M. N., Lean, M. E. J., Ashihara, H., & Crozier, A. (2014) · Food Funct. · doi:10.1039/c4fo00042k · Cited by 537
Wikoff, D. S., Welsh, B. T., Henderson, R. G., Brorby, G. P., Britt, J. K., Myers, E. F., Goldberger, J. J., Lieberman, H. R., O’Brien, C. P., Peck, J. D., et al. (2017) · Food and Chemical Toxicology · doi:10.1016/j.fct.2017.04.002 · Cited by 473
The clinical toxicology of caffeine: A review and case study
Willson, C. (2018) · Toxicology Reports · doi:10.1016/j.toxrep.2018.11.002 · Cited by 289
Metadata
- 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
- 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 (medical) › 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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