D9-Caffeine

Deuterium-substituted isotopologue of caffeine

d9-Caffeine

Names
IUPAC name

1,3,7-Tris(trideuteriomethyl)purine-2,6-dione

Other names

Caffeine-d9

Identifiers

CAS Number

* 72238-85-8

3D model (JSmol)

* Interactive image

PubChem CID

* 13001304

SMILES

* [2H]C([2H])([2H])N1C=NC2=C1C(=O)N(C(=O)N2C([2H])([2H])[2H])C([2H])([2H])[2H]

Properties

Chemical formula

| C8H10N4O2
Molar mass | 194.194 g·mol−1

Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Infobox references

Chemical compound

d9-Caffeine is a deuterium-substituted isotopologue of caffeine. It shares identical chemical and structural properties with conventional caffeine.[1] except for the substitution of some or all of its hydrogen atoms with deuterium, a naturally occurring, non-toxic, stable, heavy isotope of hydrogen. Specifically, in d9-caffeine, the nine hydrogens contained in the three methyl groups of conventional caffeine have been replaced with deuterium.

d9-Caffeine shares the xanthine backbone structure of conventional caffeine and belongs to the methylxanthine group of alkaloid compounds. It retains the physiological characteristics of caffeine as a central nervous system stimulant.[2] However, the presence of deuterium in the methyl groups alters its pharmacokinetics, rendering it less susceptible to the typical metabolic pathways that quickly metabolize conventional caffeine into its active metabolites.[3]

## Synthesis

[edit]

Deuterium, also known as hydrogen-2, 2H, or heavy hydrogen, is a stable, naturally occurring non-radioactive isotope of hydrogen.[4][full citation needed] Deuteration, also referred to as deuterium enrichment, involves the substitution of hydrogen atoms with deuterium within a molecule. In d9-caffeine, deuterium is introduced 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[1][2] of conventional caffeine but with altered pharmacokinetics.[2][3][5][6]

## Early history

[edit]

Deuterated forms of caffeine, including d9-caffeine, have been historically used as analytical reference standards in tandem liquid chromatography/mass spectrometry 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 higher molecular weight.[7]

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.,[6] which demonstrated d9-caffeine to have a prolonged half-life in rodents relative to regular 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.[5]

## Pharmacokinetics: metabolism

[edit]

d9-Caffeine exhibits a prolonged systemic exposure in rats, with a similar Cmax and a 44-77% higher total exposure. In rats, d9-caffeine freely crosses the blood-brain barrier.[2]

In single-dose comparisons in humans, d9-caffeine exhibited a 29%–43% higher Cmax 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 paraxanthine, theobromine, and theophylline.[3]

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.[3]

## Pharmacodynamics: adenosine receptor affinity

[edit]

Caffeine exerts its psychoactive and sympathomimetic effects by acting as an antagonist at adenosine receptors.[8] 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.[2]

## Safety and tolerance

[edit]

d9-Caffeine was non-genotoxic in both the Ames’s bacterial reverse mutation assay and mammalian cell micronucleus assay.[2] In a human clinical study, d9-caffeine was well tolerated with a safety profile similar to conventional caffeine.[3]

## References

[edit]

1. ^ a b "Caffeine-d9 (1,3,7-trimethyl-d9)". www.cdnisotopes.com. Retrieved 2024-08-31.
2. ^ a b c d e f Parente, Ryan M.; Tarantino, Paul M.; Sippy, Bradford C.; Burdock, George A. (2022). "Pharmacokinetic, pharmacological, and genotoxic evaluation of deuterated caffeine". Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association. 160: 112774. doi:10.1016/j.fct.2021.112774. ISSN 1873-6351. PMID 34974129.
3. ^ a b c d e Sherman, Mary M.; Tarantino, Paul M.; Morrison, Dennis N.; Lin, Chun-Han; Parente, Ryan M.; Sippy, Bradford C. (2022). "A double-blind, randomized, two-part, two-period crossover study to evaluate the pharmacokinetics of caffeine versus d9-caffeine in healthy subjects". Regulatory Toxicology and Pharmacology: RTP. 133: 105194. doi:10.1016/j.yrtph.2022.105194. ISSN 1096-0295. PMID 35690181.
4. ^ IAEA, 2023
5. ^ a b Benchekroun, Y.; Dautraix, S.; Desage, M.; Brazier, J. L. (1997). "Deuterium isotope effects on caffeine metabolism". European Journal of Drug Metabolism and Pharmacokinetics. 22 (2): 127–133. doi:10.1007/BF03189795. ISSN 0378-7966. PMID 9248780.
6. ^ a b M.G., Horning; K.D., Haegele; K.R., Sommer; J., Nowlin; M., Stafford (1975). "Metabolic switching of drug pathways as a consequence of deuterium substitution". IAEA.
7. ^ Chen, Feng; Hu, Zhe-Yi; Parker, Robert B.; Laizure, S. Casey (2017). "Measurement of caffeine and its three primary metabolites in human plasma by HPLC-ESI-MS/MS and clinical application". Biomedical Chromatography: BMC. 31 (6). doi:10.1002/bmc.3900. ISSN 1099-0801. PMC 5415443. PMID 27864843.
8. ^ Ribeiro, Joaquim A.; Sebastião, Ana M. (2010). "Caffeine and adenosine". Journal of Alzheimer's Disease: JAD. 20 Suppl 1: S3–15. doi:10.3233/JAD-2010-1379. hdl:10451/6361. ISSN 1875-8908. PMID 20164566.

*[CID]: Compound ID