Rapid appearance of caffeine in plasma of rats exposed to e-cigarette smoke, analyzed using a validated LC-MS/MS method

Although electronic cigarettes (e-cigarettes) that enable inhalation of caffeine (Caf) are commercially available, the pharmacokinetic (PK) properties of Caf intake via e-cigarette smoking are unclear. The present study used a validated LC-MS/MS method to compare the PK parameters of Caf and its metabolites (Cafs) in rat plasma after oral (p.o.) administration of Caf and exposure to e-cigarette smoke. The LC-MS/MS method was validated for Caf and metabolites such as paraxanthine (PX), theophylline (TP), theobromine, 1,3,7-trimethyluric acid, 3-methylxanthine, 1,3-dimethyluric acid, and 1,7-dimethyluric acid. Quantitation of Cafs in deproteinated rat plasma was achieved. Rats were exposed to e-cigarette smoke for 1 and 3 min, and then plasma was collected until 90 min. Although the Caf exposure dose for rats was estimated as very low, quantitation of Caf, PX, and TP was possible using the proposed LC-MS/MS method. The maximum concentrations of Caf after 1 and 3 min of exposure to e-cigarette smoke were similar to those observed after p.o. administration of 40 and 90 μg/kg, respectively. Furthermore, PK parameters such as the concentration peak time (3.0 min for 1- and 3-min exposure) and absorption rate constant (0.62 for 1 min and 0.91 min^-1 for 3 min) for e-cigarette smoke exposure differed significantly from p.o. administration (50.0 min and 36.7 min, and 0.045 and 0.070 min^-1) (P < 0.05). By contrast, no difference was observed between PX and TP. This is the first report demonstrating the rapid appearance of Caf in rat plasma after exposure to e-cigarette smoke.