Assessment of the Drug-Drug Interaction Potential Between Theacrine and Caffeine in Humans

Abstract

Objective: Theacrine, a methylurate class purine alkaloid, triggers diverse pharmacologic responses, including psychostimulatory activity by modulation of adenosinergic and dopaminergic pathways. In a double-blind, placebo-controlled study, theacrine increased energy, concentration, and mood, while reducing fatigue. Because caffeine, a methylxanthine purine alkaloid, is frequently coadministered with theacrine, we sought to determine if a pharmacokinetic and/or pharmacodynamic interaction existed between theacrine and caffeine. Methods: Eight healthy adults received theacrine, as TeaCrine® (25 or 125 mg), caffeine (150 mg), or a combination of theacrine (125 mg) and caffeine (150 mg) in a randomized, double-blind crossover study. Blood samples were collected over a 24-hour period and analyzed by Liquid chromatrography-mass spectrometry/mass spectrometry (LC-MS/MS) for theacrine, caffeine, and paraxanthine. Pharmacodynamic response markers, heart rate and blood pressure, were recorded. Results: Theacrine pharmacokinetics was similar following administration of theacrine alone. Caffeine coadministration increased maximum plasma concentration and area under the curve of theacrine without altering theacrine half-life. Theacrine had no impact on caffeine or paraxanthine pharmacokinetics. There was no difference between treatment groups with regard to heart rate or systolic/diastolic blood pressure. Conclusions: Coadministration of theacrine and caffeine results in a clinically significant pharmacokinetic interaction, viz., increased theacrine exposure. Enhanced oral bioavailability is the most likely mechanism by which caffeine alters theacrine exposure. However, further studies examining the contribution of presystemic elimination mechanisms, for example, efflux transport and/or gut metabolism, to theacrine bioavailability are needed to confirm the exact mechanism(s). Hemodynamic parameters were unaltered despite the pharmacokinetic interaction, suggesting that coadministration of caffeine and theacrine is safe at the doses administered.

Keywords: caffeine; pharmacokinetics; theacrine.

Conflict of interest statement

R.J.B. and C.R.Y. have received research funding from Compound Solutions, Inc., including this study. These contracts paid for direct and indirect costs, as well as salary. This study was funded by Compound Solutions, Inc., who was consulted in the design of the study. All other authors have no competing interests.

Figures

FIG. 1.

Individual plasma concentrations of theacrine after a single oral dose of (A) theacrine 25 mg, (B) theacrine 125 mg, and (C) theacrine 125 mg plus caffeine 150 mg.

FIG. 2.

Forest plot illustrating the probability of interaction magnitude between theacrine and caffeine using 90% confidence intervals about the geometric mean ratio of the observed pharmacokinetic parameters following a single theacrine dose (●–25mg, ■–125 mg) alone or in combination with caffeine (150 mg). Abbreviations: MRT0→∞, mean residence time zero to infinity; CL/F, oral clearance; Vz/F, oral volume of distribution; AUC0→∞, area under the curve from zero to time infinity (dose normalized); Cmax, maximum plasma concentration (dose normalized); Tmax, time to reach maximum plasma concentration.

FIG. 3.

Individual plasma concentrations of caffeine after single oral dose of (A) caffeine 150 mg and (B) theacrine 125 mg plus caffeine 150 mg.

FIG. 4.

Forest plot illustrating the probability of interaction magnitude between caffeine and theacrine using 90% confidence intervals about the geometric mean ratio of the observed pharmacokinetic parameters following a single caffeine dose (150 mg) alone or in combination with theacrine (125 mg). Abbreviations: MRT0→∞, mean residence time zero to infinity; CL/F, oral clearance; Vz/F, oral volume of distribution; AUC0→∞, area under the curve from zero to time infinity (dose normalized); Cmax, maximum plasma concentration (dose normalized); Tmax, time to reach maximum plasma concentration.

FIG. 5.

Mean values in heart rate (A), systolic blood pressure (B), diastolic blood pressure (C), and rate-pressure product (D) after single-dose theacrine 25 mg (●), theacrine 125 mg (■), caffeine 150 mg (♦), or theacrine 125 mg plus caffeine 150 mg (▲). Data are presented as mean ± standard deviation.