Figure 5
‘Real-world’ application of heart:liver models to detect metabolite driven PD effects. (a) Overview of the preclinical in vitro and in vivo QT data for both the parent compound (AZ12818677) and its metabolite (AZ12864610), concentration-effect curves for hERG activity and in vivo QT prolongation in the Guinea pig, n ≥ 3. (b) Schematic of AZ12818677 (parent) and AZ12864610 (metabolite) effects on QT prolongation. (c) Representative field potential traces following 0.1% DMSO (black), 10 µM (green) and 0.1 µM (red) of the parent compound in the heart:liver model. (d) Concentration-effect curves of the parent compound FPD response in both the heart only (black) and heart:liver (green) models following 24 hours treatment, n ≥ 3 (in the heart:liver model at concentrations ≥30 µM, arrhythmic events were observed in two out of three replicates). (e) Representative field potential traces following 0.1% DMSO (black) and 1 µM (red) of the metabolite in the heart only model. (f) Representative field potential traces following 10 µM (green) of the metabolite in the heart only model. (g) Concentration-effect curve of the metabolite FPD response in the heart only model, arrhythmias were observed at concentrations ≥ 3 µM, n ≥ 3. (h) Cell viability in both the heart and liver cellular chambers in both the heart only (parent: black; metabolite: blue) and heart:liver models (heart: green; liver: red) following 24 hours, n = 2. Individual data points plotted.
