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into each of the three methyl groups, which are then integrated into the xanthine backbone at positions 1, 3, and 7 (resulting in 1, 3, 7-trideuteriomethyl xanthine-d9). This process yields a deuterated variant that maintains the identical structure and physiochemical properties of conventional caffeine but with altered pharmacokinetics.
427:
Deuterium, also known as hydrogen-2, H, or heavy hydrogen, is a stable, naturally occurring non-radioactive isotope of hydrogen. Deuteration, also referred to as deuterium enrichment, involves the substitution of hydrogen atoms with deuterium within a molecule. In d9-caffeine, deuterium is introduced
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caffeine. Subsequent in vitro experiments with rat hepatocytes demonstrated that deuterium substitution of caffeine can result in significant shunting to or away from various downstream metabolites of caffeine depending on the deuterium placement, with d9-caffeine showing the most pronounced effect.
444:
detection systems to detect and quantify the presence of caffeine. Owing to its structural and physiochemical similarities, d9-caffeine elutes in a liquid chromatography system at the same rate as conventional caffeine but can be differentiated from caffeine via mass spectrometry due to its slightly
448:
The kinetic isotopic effect of substitution of deuterium for hydrogen within the caffeine molecule and its potential role in altering caffeine’s pharmacokinetics was first described by
Horning et al., which demonstrated d9-caffeine to have a prolonged half-life in rodents relative to regular
108:
512:
d9-Caffeine was non-genotoxic in both the Ames’s bacterial reverse mutation assay and mammalian cell micronucleus assay. In a human clinical study, d9-caffeine was well tolerated with a safety profile similar to conventional caffeine.
487:
Unlike conventional caffeine, the relative exposure of d9-caffeine was similar in slow versus rapid metabolizers of caffeine, while the relative exposure of caffeine is markedly higher in slow metabolizers.
504:. d9-Caffeine was assessed for human adenosine receptor antagonism at the four receptor subtypes: A1, A2A, A2B, and A3, and found to have similar adenosine receptor affinity as caffeine.
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626:"A double-blind, randomized, two-part, two-period crossover study to evaluate the pharmacokinetics of caffeine versus d9-caffeine in healthy subjects"
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and 4-5-fold higher total exposure than caffeine, and a 5-10-fold reduction in the relative exposure to the active metabolites of caffeine such as
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stimulant. However, the presence of deuterium in the methyl groups alters its pharmacokinetics, rendering it less susceptible to the typical
388:. It shares identical chemical and structural properties with conventional caffeine. except for the substitution of some or all of its
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Deuterated forms of caffeine, including d9-caffeine, have been historically used as analytical reference standards in tandem
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Food and
Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association
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Sherman, Mary M.; Tarantino, Paul M.; Morrison, Dennis N.; Lin, Chun-Han; Parente, Ryan M.; Sippy, Bradford C. (2022).
756:"Measurement of caffeine and its three primary metabolites in human plasma by HPLC-ESI-MS/MS and clinical application"
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backbone structure of conventional caffeine and belongs to the methylxanthine group of
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Parente, Ryan M.; Tarantino, Paul M.; Sippy, Bradford C.; Burdock, George A. (2022).
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of hydrogen. Specifically, in d9-caffeine, the nine hydrogens contained in the three
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570:"Pharmacokinetic, pharmacological, and genotoxic evaluation of deuterated caffeine"
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737:"Metabolic switching of drug pathways as a consequence of deuterium substitution"
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InChI=1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3/i1D3,2D3,3D3
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In single-dose comparisons in humans, d9-caffeine exhibited a 29%–43% higher C
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M.G., Horning; K.D., Haegele; K.R., Sommer; J., Nowlin; M., Stafford (1975).
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Caffeine exerts its psychoactive and sympathomimetic effects by acting as an
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and a 44-77% higher total exposure. In rats, d9-caffeine freely crosses the
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d9-Caffeine exhibits a prolonged systemic exposure in rats, with a similar C
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that quickly metabolize conventional caffeine into its active metabolites.
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compounds. It retains the physiological characteristics of caffeine as a
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atoms with deuterium, a naturally occurring, non-toxic, stable, heavy
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Chen, Feng; Hu, Zhe-Yi; Parker, Robert B.; Laizure, S. Casey (2017).
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Except where otherwise noted, data are given for materials in their
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Benchekroun, Y.; Dautraix, S.; Desage, M.; Brazier, J. L. (1997).
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of conventional caffeine have been replaced with deuterium.
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European
Journal of Drug Metabolism and Pharmacokinetics
687:"Deuterium isotope effects on caffeine metabolism"
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811:Ribeiro, Joaquim A.; Sebastião, Ana M. (2010).
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27:Deuterium-substituted isotopologue of caffeine
492:Pharmacodynamics: adenosine receptor affinity
54:1,3,7-Tris(trideuteriomethyl)purine-2,6-dione
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291:C()()N1C=NC2=C1C(=O)N(C(=O)N2C()())C()()
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630:Regulatory Toxicology and Pharmacology
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270:Key: RYYVLZVUVIJVGH-GQALSZNTSA-N
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817:Journal of Alzheimer's Disease: JAD
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534:"Caffeine-d9 (1,3,7-trimethyl-d9)"
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358:(at 25 °C , 100 kPa).
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149:23935581.html : 23935581
453:Pharmacokinetics: metabolism
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445:higher molecular weight.
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813:"Caffeine and adenosine"
403:d9-Caffeine shares the
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819:. 20 Suppl 1: S3–15.
438:liquid chromatography
871:Deuterated compounds
508:Safety and tolerance
538:www.cdnisotopes.com
502:adenosine receptors
463:blood-brain barrier
348: g·mol
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703:10.1007/BF03189795
417:metabolic pathways
362:Infobox references
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370:Chemical compound
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541:. Retrieved
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482:theophylline
474:paraxanthine
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382:isotopologue
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129:CHEBI:177330
68:Identifiers
60:Other names
31:d9-Caffeine
478:theobromine
374:d9-Caffeine
300:Properties
167:100.189.601
62:Caffeine-d9
18:D9-caffeine
865:Categories
834:10451/6361
672:IAEA, 2023
636:: 105194.
580:: 112774.
543:2024-08-31
517:References
498:antagonist
341:Molar mass
140:ChemSpider
96:3D model (
85:72238-85-8
75:CAS Number
51:IUPAC name
843:1875-8908
780:1099-0801
711:0378-7966
652:1096-0295
594:1873-6351
423:Synthesis
378:deuterium
188:663-277-2
180:EC Number
876:Caffeine
851:20164566
798:27864843
660:35690181
602:34974129
409:alkaloid
405:xanthine
390:hydrogen
386:caffeine
211:13001304
789:5415443
719:9248780
394:isotope
346:194.194
198:PubChem
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480:, and
284:SMILES
45:Names
766:(6).
376:is a
259:InChI
120:ChEBI
98:JSmol
847:PMID
839:ISSN
794:PMID
776:ISSN
741:IAEA
715:PMID
707:ISSN
656:PMID
648:ISSN
598:PMID
590:ISSN
829:hdl
821:doi
784:PMC
768:doi
699:doi
638:doi
634:133
582:doi
578:160
500:at
470:max
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459:max
384:of
228:EPA
201:CID
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334:2
331:O
328:4
325:N
319:H
316:8
313:C
230:)
226:(
100:)
20:)
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