Effects of Serum and Compound Preparation Methods on Delayed Repolarization Evaluation With Human iPSC-CMs
Abstract Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in the Comprehensive in vitro Proarrhythmia Assay (CiPA). The notable difference of the electrophysiological (EP) responses of hiPSC-CMs in serum and serum-free media (SFM) is puzzling and may impact regulatory decision-making on the cardiac safety of candidate drugs in inducing QT prolongation and torsade de pointes (TdP). In this study, we compared the EP responses of hiPSC-CMs to 10 CiPA compounds and moxifloxacin in serum and SFM; explained the potential reason behind the different EP responses—abiotic compound loss to plastic tubes/plates of hydrophobic compounds prepared in SFM; and investigated the impact of compound preparation methods on drug bioavailability in exposure media, which affects the TdP risk prediction of drugs tested in serum-containing and SFM. For assays to be conducted in SFM, awareness of abiotic compound loss of hydrophobic compounds in serum-free preparations is critical for delay repolarization evaluation and data extrapolation from in vitro to in vivo.
- Research Organization:
- Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC)
- DOE Contract Number:
- SC0014664
- OSTI ID:
- 1982723
- Journal Information:
- Toxicological Sciences, Vol. 188, Issue 1; ISSN 1096-6080
- Publisher:
- Oxford University Press
- Country of Publication:
- United States
- Language:
- English
Similar Records
Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block
Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation