FIGURE 4.

Cisapride metabolism in hiPSC-Heps in conventional cell culture and liver MPS. (A) Metabolism of the arrhythmogenic drug cisapride into norcisapride by CYP3A4 in the liver (top). Drug–drug or drug–food interactions can inhibit this metabolic reaction. Ketoconazole (Keto) inhibits CYP3A4-driven metabolism of cisapride into norcisapride (bottom). (B) Relative metabolite formation clearance for cisapride in hiPSC-Heps in conventional cell culture within 30 min. Data are presented as the mean ± standard deviation from three independent experiments with two biological replicates each. Unpaired Student’s t test, ***p < 0.0003, ****p < 0.0001. Experiments were performed in cell culture dishes with low drug absorption. (C) Percentage of cisapride metabolized to norcisapride with and without ketoconazole. Data are presented as the mean ± standard error of mean for two biological replicates of one experiment. The experiment was performed in cell culture dishes with low drug absorption. (D) CYP3A4 activity in the liver MPS measured with a luminescence assay with and without ketoconazole. Data are presented as the mean ± standard error of mean for three independent experiments. (E) Change in cisapride concentration in the liver MPS media channel and the supernatant of conventional cell cultures (2D). Data are presented as the mean ± standard error of mean for three independent experiments.