Paraxanthine

Last updated

Paraxanthine
Paraxanthine structure.svg
Skeletal formula of paraxanthine
Paraxanthine 3D ball.png
Ball-and-stick model of the paraxanthine model
Clinical data
Other names1,7-Dimethylxanthine; 3-Desmethylcaffeine; 3-Demethylcaffeine
Routes of
administration 		Oral [1]
Drug class Adenosine receptor antagonist; Phosphodiesterase inhibitor; Stimulant; Wakefulness-promoting agent
Pharmacokinetic data
Metabolites 1-Methylxanthine, others [2]
Elimination half-life 3.1 hours [2] [1]
Excretion Urine: 60% unchanged [2]
Identifiers
  • 1,7-dimethyl-3H-purine-2,6-dione
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.009.339 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C7H8N4O2
Molar mass 180.167 g·mol−1
3D model (JSmol)
Melting point 351 to 352 °C (664 to 666 °F)
  • O=C2Nc1ncn(c1C(=O)N2C)C
  • InChI=1S/C7H8N4O2/c1-10-3-8-5-4(10)6(12)11(2)7(13)9-5/h3H,1-2H3,(H,9,13) Yes check.svgY
  • Key:QUNWUDVFRNGTCO-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Paraxanthine, also known as 1,7-dimethylxanthine, is a stimulant drug of the xanthine family related to caffeine. [2] It is the major metabolite of caffeine and is a positional isomer of theobromine and theophylline. [2] The drug acts as an adenosine receptor antagonist similarly to caffeine. [2] Unlike caffeine, theobromine, and theophylline, paraxanthine occurs in only trace amounts in plants like Coffea arabica . [2] It started being sold in energy drinks as an alternative to caffeine in the United States in 2023. [3] [4]

Contents

Toxicity

Paraxanthine is believed to exhibit a lower toxicity than caffeine and the caffeine metabolite, theophylline. [5] [6] In a mouse model, intraperitoneal paraxanthine doses of 175 mg/kg/day did not result in animal death or overt signs of stress; [7] by comparison, the intraperitoneal LD50 for caffeine in mice is reported at 168 mg/kg. [8] In in vitro cell culture studies, paraxanthine is reported to be less harmful than caffeine and the least harmful of the caffeine-derived metabolites in terms of hepatocyte toxicity. [9]

As with other methylxanthines, paraxanthine is reported to be teratogenic when administered in high doses; [7] but it is a less potent teratogen as compared to caffeine and theophylline. A mouse study on the potentiating effects of methylxanthines coadministered with mitomycin C on teratogenicity reported the incidence of birth defects for caffeine, theophylline, and paraxanthine to be 94.2%, 80.0%, and 16.9%, respectively; additionally, average birth weight decreased significantly in mice exposed to caffeine or theophylline when coadministered with mitomycin C, but not for paraxanthine coadministered with mitomycin C. [10]

Paraxanthine was reported to be significantly less clastogenic compared to caffeine or theophylline in an in vitro study using human lymphocytes. [11]

Pharmacology

Pharmacodynamics

Like caffeine, paraxanthine is a psychoactive central nervous system (CNS) stimulant. [12]

Studies indicate that, similar to caffeine, simultaneous antagonism of adenosine receptors [13] is responsible for paraxanthine's stimulatory effects. Paraxanthine adenosine receptor binding affinity (21 μM for A1, 32 μM for A2A, 4.5 μM for A2B, and >100 μM for A3) is similar or slightly stronger than caffeine, but weaker than theophylline. [2]

Paraxanthine is a selective inhibitor of cGMP-preferring phosphodiesterase (PDE9) activity [14] and is hypothesized to increase glutamate and dopamine release by potentiating nitric oxide signaling. [15] Activation of a nitric oxide-cGMP pathway may be responsible for some of the behavioral effects of paraxanthine that differ from those associated with caffeine. [14]

Paraxanthine is a competitive nonselective phosphodiesterase inhibitor [16] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha [17] [18] and leukotriene [19] synthesis, and reduces inflammation and innate immunity. [19]

Unlike caffeine, paraxanthine acts as an enzymatic effector of Na+/K+ ATPase. As a result, it is responsible for increased transport of potassium ions into skeletal muscle tissue. [20] Similarly, the compound also stimulates increases in calcium ion concentration in muscle. [21]

Pharmacokinetics

Paraxanthine is not known to be produced by plants [22] but is observed in nature as a metabolite of caffeine in animals and some species of bacteria. [12]

Paraxanthine is the primary metabolite of caffeine in humans and other animals, such as mice. [23] Shortly after ingestion, roughly 84% of caffeine is metabolized into paraxanthine by hepatic cytochrome P450, which removes a methyl group from the N3 position of caffeine. [24] [25] [12] After formation, paraxanthine can be broken down to 7-methylxanthine by demethylation of the N1 position, [26] which is subsequently demethylated into xanthine or oxidized by CYP2A6 and CYP1A2 into 1,7-dimethyluric acid. [12] In another pathway, paraxanthine is broken down into 5-acetylamino-6-formylamino-3-methyluracil through N-acetyl-transferase 2, which is then broken down into 5-acetylamino-6-amino-3-methyluracil by non-enzymatic decomposition. [27] In yet another pathway, paraxanthine is metabolized CYP1A2 forming 1-methyl-xanthine, which can then be metabolized by xanthine oxidase to form 1-methyl-uric acid. [27]

The pharmacokinetic parameter for paraxanthine are similar to those for caffeine, but differ significantly from those for theobromine and theophylline, the other major caffeine-derived methylxanthine metabolites in humans.

Comparative pharmacokinetics of caffeine and caffeine-derived methylxanthines [1]
Plasma half-life

(t1/2; hr)

Volume of distribution

(Vss,unbound; l/kg)

Plasma clearance

(CL; ml/min/kg)

Caffeine 4.1 ± 1.31.06 ± 0.262.07 ± 0.96
Paraxanthine3.1 ± 0.81.18 ± 0.372.20 ± 0.91
Theobromine 7.2 ± 1.60.79 ± 0.151.20 ± 0.40
Theophylline 6.2 ± 1.40.77 ± 0.170.93 ± 0.22

Chemistry

Analogues

Analogues of paraxanthine (1,7-dimethylxanthine) include caffeine (1,3,7-trimethylxanthine), theophylline (1,3-dimethylxanthine), and theobromine (3,7-dimethylxanthine), among many others. [2]

References

  1. 1 2 3 Lelo A, Birkett DJ, Robson RA, Miners JO (August 1986). "Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man". British Journal of Clinical Pharmacology. 22 (2): 177–182. doi:10.1111/j.1365-2125.1986.tb05246.x. PMC   1401099 . PMID   3756065.
  2. 1 2 3 4 5 6 7 8 9 Arnaud MJ (2011). "Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man". In Fredholm BB (ed.). Methylxanthines. Handbook of Experimental Pharmacology. Vol. 200. Berlin, Heidelberg: Springer. pp. 33–91. doi:10.1007/978-3-642-13443-2_3. ISBN   978-3-642-13443-2. ISSN   1865-0325. PMID   20859793 . Retrieved 25 October 2026.
  3. ↑ Licosa MD (24 February 2026). "Kim Kardashian Joins Relaunch Of UPDATE Caffeine-Free Energy Drink". Forbes. Retrieved 25 October 2026.
  4. ↑ Intner K (5 August 2026). "What Is Paraxanthine? All About the Caffeine Alternative in Kim Kardashian's Energy Drink". Harper's BAZAAR. Harper's BAZAAR. Retrieved 25 October 2026.
  5. ↑ Benowitz NL, Jacob P, Mayan H, Denaro C (December 1995). "Sympathomimetic effects of paraxanthine and caffeine in humans". Clinical Pharmacology and Therapeutics. 58 (6): 684–691. doi:10.1016/0009-9236(95)90025-X. PMID   8529334. S2CID   22747642.
  6. ↑ Institute of Medicine (US) Committee on Military Nutrition Research (2001). Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. Washington (DC): National Academies Press (US). ISBN   978-0-309-08258-7. PMID   25057583.
  7. 1 2 York RG, Randall JL, Scott WJ (December 1986). "Teratogenicity of paraxanthine (1,7-dimethylxanthine) in C57BL/6J mice". Teratology. 34 (3): 279–282. doi:10.1002/tera.1420340307. PMID   3798364.
  8. ↑ Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. 1987.
  9. ↑ Gressner OA, Lahme B, Siluschek M, Gressner AM (July 2009). "Identification of paraxanthine as the most potent caffeine-derived inhibitor of connective tissue growth factor expression in liver parenchymal cells". Liver International. 29 (6): 886–897. doi:10.1111/j.1478-3231.2009.01987.x. PMID   19291178. S2CID   32926935.
  10. ↑ Nakatsuka T, Hanada S, Fujii T (October 1983). "Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice". Teratology. 28 (2): 243–247. doi:10.1002/tera.1420280214. PMID   6417813.
  11. ↑ Weinstein D, Mauer I, Katz ML, Kazmer S (February 1975). "The effect of methylxanthines on chromosomes of human lyphocytes in culture". Mutation Research/Environmental Mutagenesis and Related Subjects. 31 (1): 57–61. doi:10.1016/0165-1161(75)90064-3. PMID   1128545.
  12. 1 2 3 4 Mazzafera P (May 2004). "Catabolism of caffeine in plants and microorganisms". Frontiers in Bioscience. 9 (1–3): 1348–1359. doi: 10.2741/1339 . PMID   14977550.
  13. ↑ Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Progress in Clinical and Biological Research. 230 (1): 41–63. PMID   3588607.
  14. 1 2 Orrú M, Guitart X, Karcz-Kubicha M, Solinas M, Justinova Z, Barodia SK, et al. (April 2013). "Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans". Neuropharmacology. 67: 476–484. doi:10.1016/j.neuropharm.2012.11.029. PMC   3562388 . PMID   23261866.
  15. ↑ Ferré S, Orrú M, Guitart X (June 2013). "Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission". Journal of Caffeine Research. 3 (2): 72–78. doi:10.1089/jcr.2013.0006. PMC   3680978 . PMID   24761277.
  16. ↑ Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". The Journal of Allergy and Clinical Immunology. 108 (5): 671–680. doi: 10.1067/mai.2001.119555 . PMID   11692087.
  17. ↑ Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (June 2008). "Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition". Clinics. 63 (3). Sao Paulo, Brazil: 321–328. doi:10.1590/S1807-59322008000300006. PMC   2664230 . PMID   18568240.
  18. ↑ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". American Journal of Respiratory and Critical Care Medicine. 159 (2): 508–511. doi:10.1164/ajrccm.159.2.9804085. PMID   9927365.
  19. 1 2 Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (January 2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology. 174 (2). Baltimore: 589–594. doi: 10.4049/jimmunol.174.2.589 . PMID   15634873.
  20. ↑ Hawke TJ, Willmets RG, Lindinger MI (November 1999). "K+ transport in resting rat hind-limb skeletal muscle in response to paraxanthine, a caffeine metabolite". Canadian Journal of Physiology and Pharmacology. 77 (11): 835–843. doi:10.1139/y99-095. PMID   10593655.
  21. ↑ Hawke TJ, Allen DG, Lindinger MI (December 2000). "Paraxanthine, a caffeine metabolite, dose dependently increases [Ca(2+)](i) in skeletal muscle". Journal of Applied Physiology. 89 (6). Bethesda: 2312–2317. doi: 10.1152/jappl.2000.89.6.2312 . PMID   11090584. S2CID   11369121.
  22. ↑ Stavric B (August 1988). "Methylxanthines: toxicity to humans. 3. Theobromine, paraxanthine and the combined effects of methylxanthines". Food and Chemical Toxicology. 26 (8): 725–733. doi:10.1016/0278-6915(88)90073-7. PMID   3058562.
  23. ↑ Fuhr U, Doehmer J, Battula N, Wölfel C, Flick I, Kudla C, et al. (October 1993). "Biotransformation of methylxanthines in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. Allocation of metabolic pathways to isoforms and inhibitory effects of quinolones". Toxicology. 82 (1–3): 169–189. Bibcode:1993Toxgy..82..169F. doi:10.1016/0300-483x(93)90064-y. PMID   8236273.
  24. ↑ Guerreiro S, Toulorge D, Hirsch E, Marien M, Sokoloff P, Michel PP (October 2008). "Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels". Molecular Pharmacology. 74 (4): 980–989. doi:10.1124/mol.108.048207. PMID   18621927. S2CID   14842240.
  25. ↑ Graham TE, Rush JW, van Soeren MH (June 1994). "Caffeine and exercise: metabolism and performance". Canadian Journal of Applied Physiology = Revue Canadienne de Physiologie Appliquee. 19 (2): 111–138. doi:10.1139/h94-010. PMID   8081318.
  26. ↑ Summers RM, Mohanty SK, Gopishetty S, Subramanian M (May 2015). "Genetic characterization of caffeine degradation by bacteria and its potential applications". Microbial Biotechnology. 8 (3): 369–378. doi: 10.1111/1751-7915.12262 . PMC   4408171 . PMID   25678373.
  27. 1 2 Preedy VR (2012). Caffeine: Chemistry, Analysis, Function and Effects. Cambridge, U.K.: Royal Society of Chemistry. ISBN   978-1-84973-475-2. OCLC   810337257.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.