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

Abstract

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%) C_max and 4-5-fold higher AUC_last than caffeine, and lower C_max, lower AUC_last, 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.

Keywords: Caffeine; Deuteration; Metabolites; Pharmacokinetics (PK); d9-caffeine.