A double-blind, randomized, two-part, two-period crossover study to evaluate the pharmacokinetics of caffeine versus d9-caffeine in healthy subjects.

The deuterium kinetic isotope effect has been used to affect the cytochrome P450 metabolism of the deuterated versions of substances. This study compares the pharmacokinetics of caffeine, a Generally Recognized As Safe food and beverage ingredient, versus d9-caffeine, a potential caffeine alternative, and their respective metabolites at two dose levels in 20 healthy adults. A single dose of 50 mg or 250 mg of caffeine, or a molar-equivalent dose of d9-caffeine, were orally administered in solution with blood samples collected for up to 48 h post-dose. Plasma concentrations of parent and metabolites were analyzed using validated LC-MS/MS methods. Both d9-caffeine and caffeine were rapidly absorbed; however, d9-caffeine exhibited a higher (ca. 29%-43%) Cmax and 4-5-fold higher AUClast than caffeine, and lower Cmax, lower AUClast, and a 5-10-fold reduction in the relative exposure to the active metabolites of caffeine. Results were consistent in normal and rapid metabolizers, and both substances were well tolerated.

Pharmacokinetic, pharmacological, and genotoxic evaluation of deuterated caffeine.

Altering caffeine's negative physiological effects and extending its duration of activity is an active area of research; however, deuteration as a means of achieving these goals is unexplored. Deuteration substitutes one or more of the hydrogen atoms of a substance with deuterium, a stable isotope of hydrogen that contains an extra neutron. Deuteration can potentially alter the metabolic profile of a substance, while maintaining its pharmacodynamic properties. d9-Caffeine is a deuterated isotopologue of caffeine with the nine hydrogens contained in the 1, 3, and 7 methyl groups of caffeine substituted with deuterium. d9-Caffeine may prove to be an alternative to caffeine that may be consumed with less frequency, at lower doses, and with less exposure to downstream active metabolites of caffeine. Characterization of d9-caffeine's genotoxic potential, pharmacodynamic, and pharmacokinetic behavior is critical in establishing how it may differ from caffeine. d9-Caffeine was non-genotoxic with and without metabolic activation in both a bacterial reverse mutation assay and a human mammalian cell micronucleus assay at concentrations up to the ICH concentration limits. d9-Caffeine exhibited a prolonged systemic and brain exposure time in rats as compared to caffeine following oral administration. The adenosine receptor antagonist potency of d9-caffeine was similar to caffeine.