Method Profile
A PFPE flow path reduces device sorption while separate intestinal and hepatic dosing measurements estimate the contributions to midazolam availability.
In vitro assessment of oral small-molecule first-pass metabolism and metabolic drug interactions.
An intestinal compartment using genome-edited CYP3A4/UGT1A1-expressing Caco-2 cells connected in series with a hepatic compartment.
Intestinal-side dosing followed by collection of liver-compartment effluent, supplemented by a separate hepatic bolus to estimate hepatic extraction.
Device material comparison
Perfluoropolyether (PFPE) and polydimethylsiloxane (PDMS) devices compared through the appearance of intact midazolam in effluent.
Drug and inhibitor conditions
Midazolam at 200 μM and 10 μM, with a ketoconazole co-administration comparison.
Compare intact drug recovery across materials, use intestinal and separate hepatic dosing to estimate compartment contributions, and assess concentration dependence and metabolic inhibition.
Material, concentration and inhibitor comparisons within a midazolam case study.
One reported test drug; replicate counts are not specified in the article abstract.
PDMS device, two midazolam concentrations and ketoconazole co-administration.
PFPE gave more than 20-fold greater appearance of intact midazolam in hepatic effluent. Estimated intestinal and hepatic availabilities were 0.96 and 0.82, both above human reference values.
A PFPE device improves recovery of intact midazolam and allows separate estimates of intestinal and hepatic availability. Those estimates remain above human reference values, indicating a need to improve metabolic activity in the system.
