Absorption of dimethoxycinnamic acid derivatives in vitro and pharmacokinetic profile in human plasma following coffee consumption

Scope: This study reports the 24 h human plasma pharmacokinetics of 3,4-dimethoxycinnamic acid (dimethoxycinnamic acid) after consumption of coffee, and the membrane transport characteristics of certain dimethoxycinnamic acid derivatives, as present in coffee. Methods and results: Eight healthy human volunteers consumed a low-polyphenol diet for 24 h before drinking 400 mL of commercially available coffee. Plasma samples were collected over 24 h and analyzed by HPLC-MS². Investigation of the mechanism of absorption and metabolism was performed using an intestinal Caco-2 cell model. For the first time, we show that dimethoxycinnamic acid appears in plasma as the free aglycone. The time to reach the C_max value of approximately 0.5 μM was rapid, T_max = 30 min, and showed an additional peak at 2-4 h for several subjects. In contrast, smaller amounts of dimethoxy-dihydrocinnamic acid (C_max ∼ 0.1 μM) peaked between 8 and 12 h after coffee intake. In the cell model, dimethoxycinnamic acid was preferentially transported in the free form by passive diffusion, and a small amount of dimethoxycinnamoylquinic acid hydrolysis was observed. Conclusion: These findings show that dimethoxycinnamic acid, previously identified in plasma after coffee consumption, was rapidly absorbed in the free form most likely by passive diffusion in the upper gastrointestinal tract.