Fig. 4.
(a) Intrinsic clearance prediction (IVIVE of CLint) from CN Bio’s 3D microtissue-based model. The solid line shows 100 % prediction accuracy and the dotted line shows the ±3 fold range. Class 1a and 2 compounds are shown in green, class 3 compounds in blue, and class 4 compounds in red (according to ECCS: extended clearance classification system). (b) Hepatic clearance prediction from Javelin Biotech’s platform using parallel tube model. (c) Idiosyncratic DILI investigation of TAK-875 on LoC: (i) MRP2 transporter activity upon treatment with TAK-875 measured by efflux of MRP2 substrate: CMFDA, (ii) Mitochondrial membrane potential shown by TMRM on day 8, (iii) ROS formation shown by CellRox on day 17, (iv) Lipid accumulation shown by AdipoRed on day 17. (Scale bars = 100 μm) (d) High-throughput OrganoPlate developed by Mimetas cultured with iHep organoids: (i) Organ channel seeded with iHep and perfusion channel contains HMEC-1 and THP-1, (ii) Cell viability (%) results for 40 out of 159 compounds with evidence of hepatotoxicity are rank ordered going left to right from least to most toxic. The viability of the remaining compounds were at vehicle control levels. Error bars are shown for vehicle and troglitazone controls (n = 8). All cultures were exposed to test compounds for 72 h at 50 μM (n = 1). Panel (a) is adapted under terms of the CC-BY license from Ref. [82] Copyright 2022, RSC. The dotted line showing the ±3 fold range was added. Panel (b) is reproduced under terms of the CC-BY license from Ref. [81] Copyright 2023, Springer. Panel (c) is adapted with permission from Ref. [55] Copyright 2019, AAAS. Panel (d) is reproduced under terms of the CC-BY license from Ref. [76] Copyright 2021, Elsevier. We have rewritten the names of the compounds in Figure (d-ii) for the better clarity of the readers. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)