Abstract
Gastric emptying is a critical determinant of the pharmacokinetics of orally administered drugs. A key limitation in studies using caffeine as a marker for gastric emptying is the requirement for prior caffeine abstinence, which can complicate study design and participant recruitment. The present study was conducted with the objective of evaluating the potential use of the methylurates methylliberine and theacrine as novel salivary markers for the assessment of gastric emptying of non-caloric liquids, in comparison to the established marker caffeine. A Salivary Tracer Technique (STT) was employed in a crossover study that involved twelve healthy volunteers. The subjects participating in the study were under fasted state conditions according to the guidelines of the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) when they received ice capsules containing either caffeine, methylliberine, theacrine, or a combination of these three substances. Salivary samples were collected at predetermined intervals over 24 h in order to analyse their pharmacokinetic profiles. The results demonstrated a rapid absorption, with maximum salivary concentrations (c(max)) reached within 30 min for all markers. It is noteworthy that methylliberine and theacrine exhibited strong correlations with caffeine in their absorption profiles, with Pearson correlation coefficients of r = 0.9973 and r = 0.9865, respectively, during the initial 40 min post-administration. Furthermore, the elimination half-lives (t(1/2)) of methylliberine and theacrine were found to differ significantly, with methylliberine exhibiting a rapid elimination profile (t(1/2) = 1.15 ± 0.12 h) in comparison to theacrine (t(1/2) = 21.00 ± 7.55 h). These results support methylliberine and theacrine as promising non-invasive markers of gastric emptying, offering viable alternatives to caffeine that may eliminate the need for abstinence and may allow for more efficient multi-tracer pharmacokinetic studies.