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This study describes the characterization of pharmacokinetic (PK) properties of acetaminophen (APAP) in the Two-Organ-Chip platform (2-OC), a two-chamber device able to cultivate 3D tissues under flow. The APAP intestinal absorption and hepatic metabolism were emulated by human intestine and liver equivalents respectively. The intestinal barrier was produced using Caco-2 and HT-29 cells. The liver spheroids were produced with HepaRG and HHSTeC cells. Cell viability and toxicity were assessed by MTT assay, histology, confocal immunohistochemistry, and multiparametric high content analysis. Gene expression of intestine and liver equivalents were assessed by real-time PCR. Three assemblies of Microphysiological System (MPS) were applied: Intestine 2-OC, Liver 2-OC, and Intestine/Liver 2-OC. The oral administration was emulated by APAP placement over the apical side of the intestinal barrier and the intravenous routes were mimic by the application in the medium. Samples were analyzed by HPLC/UV. APAP 12 μM or 2 μM treatment did not induce cytotoxicity for the intestinal barrier (24 h time-point) or for the liver spheroids 12 h time-point), respectively. All preparations showed slower APAP absorption than reported for humans: Peak time (Tmax) = 12 h for Intestine 2-OC and 6 h for Intestine/Liver 2-OC in both static and dynamic conditions, against reported Tmax of 0,33 to 1,4 h after oral administration to humans. APAP metabolism was also slower than reported for humans. The APAP half-life (T 1/2 ) was 12 h in the dynamic Liver 2-OC, against T 1/2  = 2 ± 0,4 h reported for humans. Samples taken from the Liver 2-OC static preparation did not show APAP concentration decrease. These findings show the MPS capability and potential to emulate human PK properties and highlight the critical role of mechanical stimulus over cell functionality, especially by demonstrating the clear positive influence of the microfluidic flow over the liver equivalents metabolic performance., (© 2018 Published by Elsevier B.V.)