Skeletal formula of paraxanthine
Ball-and-stick model of the paraxanthine model
IUPAC name
Other names
3D model (JSmol)
ECHA InfoCard 100.009.339 Edit this at Wikidata
  • InChI=1S/C7H8N4O2/c1-10-3-8-5-4(10)6(12)11(2)7(13)9-5/h3H,1-2H3,(H,9,13) checkY
  • InChI=1/C7H8N4O2/c1-10-3-8-5-4(10)6(12)11(2)7(13)9-5/h3H,1-2H3,(H,9,13)
  • O=C2Nc1ncn(c1C(=O)N2C)C
Molar mass 180.167 g·mol−1
Melting point 351 to 352 °C (664 to 666 °F; 624 to 625 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Paraxanthine, also known as 1,7-dimethylxanthine, is a metabolite of theophylline and theobromine, two well-known stimulants found in coffee, tea, and chocolate mainly in the form of caffeine. It is a member of the xanthine family of alkaloids, which includes theophylline, theobromine and caffeine.

Production and metabolism

Paraxanthine is not known to be produced by plants[1] but is observed in nature as a metabolite of caffeine in animals and some species of bacteria.[2]

Paraxanthine is the primary metabolite of caffeine in humans and other animals, such as mice.[3] 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.[4][5][6] After formation, paraxanthine can be broken down to 7-methylxanthine by demethylation of the N1 position,[7] which is subsequently demethylated into xanthine or oxidized by CYP2A6 and CYP1A2 into 1,7-dimethyluric acid.[6] 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.[8] In yet another pathway, paraxanthine is metabolized CYPIA2 forming 1-methyl-xanthine, which can then be metabolized by xanthine oxidase to form 1-methyl-uric acid.[8]

Certain proposed synthetic pathways of caffeine make use of paraxanthine as a bypass intermediate. However, its absence in plant alkaloid assays implies that these are infrequently, if ever, directly produced by plants.[citation needed]

Pharmacology and physiological effects

This section needs more reliable medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Paraxanthine" – news · newspapers · books · scholar · JSTOR (November 2021)

Like caffeine, paraxanthine is a psychoactive central nervous system (CNS) stimulant.[2]


Studies indicate that, similar to caffeine, simultaneous antagonism of adenosine receptors[9] 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 for μM for A3) is similar or slightly stronger than caffeine, but weaker than theophylline.[10]

Paraxanthine is a selective inhibitor of cGMP-preferring phosphodiesterase (PDE9) activity[11] and is hypothesized to increase glutamate and dopamine release by potentiating nitric oxide signaling.[12] 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.[13]

Paraxanthine is a competitive nonselective phosphodiesterase inhibitor[14] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha[15][16] and leukotriene[17] synthesis, and reduces inflammation and innate immunity.[17]

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.[18] Similarly, the compound also stimulates increases in calcium ion concentration in muscle.[19]


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 (Table 1).

Table 1. Comparative pharmacokinetics of caffeine, and caffeine-derived methylxanthines[20]
Plasma Half-Life

(t1/2; hr)

Volume of Distribution

(Vss,unbound; l/kg)

Plasma Clearance

(CL; ml/min/kg)

Caffeine 4.1 ± 1.3 1.06 ± 0.26 2.07 ± 0.96
Paraxanthine 3.1 ± 0.8 1.18 ± 0.37 2.20 ± 0.91
Theobromine 7.2 ± 1.6 0.79 ± 0.15 1.20 ± 0.40
Theophylline 6.2 ± 1.4 0.77 ± 0.17 0.93 ± 0.22


Paraxanthine is a phosphodiesterase type 9 (PDE9) inhibitor and it is sold as a research molecule for this same purpose.[21]


Paraxanthine is believed to exhibit a lower toxicity than caffeine and the caffeine metabolite, theophylline.[22][23] In a mouse model, intraperitoneal paraxanthine doses of 175 mg/kg/day did not result in animal death or overt signs of stress;[24] by comparison, the intraperitoneal LD50 for caffeine in mice is reported at 168 mg/kg.[25] 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.[26]

As with other methylxanthines, paraxanthine is reported to be teratogenic when administered in high doses;[24] 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.[27]

Paraxanthine was reported to be significantly less clastogenic compared to caffeine or theophylline in an in vitro study using human lymphocytes.[28]


  1. ^ Stavric, B. (1988-01-01). "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. ISSN 0278-6915. PMID 3058562.
  2. ^ a b Mazzafera P (May 2004). "Catabolism of caffeine in plants and microorganisms". Frontiers in Bioscience. 9 (1–3): 1348–59. doi:10.2741/1339. PMID 14977550.
  3. ^ Fuhr U, Doehmer J, Battula N, Wölfel C, Flick I, Kudla C, Keita Y, Staib AH (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): 169–89. doi:10.1016/0300-483x(93)90064-y. PMID 8236273.
  4. ^ 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): 980–9. doi:10.1124/mol.108.048207. PMID 18621927. S2CID 14842240.
  5. ^ Graham TE, Rush JW, van Soeren MH (June 1994). "Caffeine and exercise: metabolism and performance". Canadian Journal of Applied Physiology. 19 (2): 111–38. doi:10.1139/h94-010. PMID 8081318.
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  14. ^ Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". The Journal of Allergy and Clinical Immunology. 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087.
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