Applicability of methylliberine as a salivary marker under postprandial conditions

Salivary pharmacokinetics provide a non-invasive alternative to blood sampling and are widely applied for the investigation of formulation performance and physiological processes such as gastric emptying. In this context, caffeine is an established salivary marker due to its robust and well characterised pharmacokinetic behaviour and low susceptibility to postprandial physiological changes, allowing its use under both fasted and fed conditions. Recently, methylliberine has been introduced as a novel salivary marker and shown to be suitable for the assessment of gastric emptying under fasted conditions, offering advantages such as a short elimination half-life and simplified study designs as caffeine abstinence is unnecessary. However, its applicability as a salivary marker under postprandial conditions has not yet been evaluated. The present study aimed to assess whether methylliberine can be applied as a salivary marker under fed state conditions in a manner comparable to caffeine. Compression-coated tablets containing 100 mg methylliberine and 25 mg caffeine were developed to prevent oral contamination and characterised in vitro. In a randomised three-way crossover study, twelve healthy volunteers received the formulation in the fasted state, after a standardized light meal and a high fat meal. Saliva samples were collected for 24 h and analysed by LC-MS/MS. Both analytes were rapidly detectable in saliva after administration. Postprandial dosing resulted in delayed t_max values for both substances, consistent with altered gastric emptying. While systemic exposure of caffeine remained unaffected by food intake, methylliberine exhibited a calorie-dependent reduction in exposure, which was statistically significant after the high-fat meal compared with fasted administration. These findings indicate that methylliberine might have limitations as a salivary marker under postprandial conditions. At the same time, its sensitivity to the physiology of the fed state identifies methylliberine as a potential substance for investigating the mechanisms of food effects.