Caco2 assay. Assessment of passive permeability and active transport of the compounds was carried out using Caco-2 cells in a 24-well CacoReady transwell plate system (ReadyCell, Barcelona, Spain). The assay was carried out in accordance with the manufacturer's instructions. Briefly, the plate was received on Day 16 post cell seeding and stored at ambient temperature in the dark. On Day 18, shipping medium was liquified by incubation at 37 °C and replaced with Caco-2 Cell Culture Medium consisting of Dulbecco's Modified Eagle's Medium, low glucose, supplemented with 10% v/v fetal bovine serum, 2 mM Lglutamine, and 100 U/mL penicillin-steptomycin. Cells were then incubated at 37 °C, 5% CO2 until day Day 21. On Day 21, trans-epithelial electrical resistance (TEER) was measured using an Evom2 voltohmmeter paired with an STX-100C electrode. All TEER measurements were >1000 ohm x cm 2 . Caco-2 cell culture medium was changed, and the cells were incubated overnight. On Day 22, the culture medium was removed, and the plate was washed with transport buffer (HBSS containing 2% BSA). For apical-tobasal assessments, the lower compartments were filled with transport buffer, and the upper compartments were filled with transport buffer containing drug at a concentration of 10 µM. For basal-to-apical assessments, the upper compartments were filled with transport buffer and the lower compartments were filled with 10 µM drug in transport buffer. 25-µL aliquots were immediately taken from each drugcontaining well and frozen at -20°C. The cells were incubated with drug for 120 minutes at 37°C, 5% CO2. At the end of incubation, 25 µL aliquots were taken from both the upper and lower compartments of each well and frozen at -20°C. Drug concentrations in the upper and lower compartments were determined by LC-MS/MS analysis and apparent permeability coefficients were calculated with the following formulas: