Herein, we found that methylliberine altered caffeine pharmacokinetics without a reciprocal interaction, which suggests caffeine may interact uniquely with different methylurates. We previously demonstrated theacrine bioavailability was enhanced by caffeine, however, caffeine pharmacokinetics were unaffected by theacrine. 458 ± 93.5 ng/mL) or oral volume of distribution (351 ± 148 vs. Methylliberine had no impact on caffeine’s maximum concentration (440 ± 140 vs. However, methylliberine co-administration resulted in decreased oral clearance (41.9 ± 19.5 vs. Methylliberine exhibited linear pharmacokinetics that were unaffected by co-administration of either caffeine or theacrine. Blood samples were collected over 24 hours and analyzed for methylliberine, theacrine, and caffeine using UPLC-MS/MS. Subjects (n = 12) received an oral dose of either methylliberine (25 or 100 mg), caffeine (150 mg), methylliberine (100 mg) plus caffeine (150 mg), or methylliberine (100 mg) plus theacrine (50 mg) using a randomized, double-blind, crossover design. Consequently, we conducted a double-blind, placebo-controlled study pharmacokinetic study in humans administered methylliberine, theacrine, and caffeine to determine methylliberine’s pharmacokinetic interaction potential with either caffeine or theacrine. We previously demonstrated that the methylxanthine caffeine increased theacrine’s oral bioavailability in humans. Methylliberine and theacrine are methylurates found in the leaves of various Coffea species and Camellia assamica var.
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