Study of time-dependent pharmacokinetics of mouse embryonic stem cell-derived cardiomyocytes for drug screening

Abstract

Core clock proteins play a significant role in maintaining physiological functions, including the metabolism in organisms in a circadian pattern. Metabolism is critical for drug efficiency and pharmacokinetics, which depend on circadian rhythm in animals and humans. Although alternative results are expected in animal experiments, there are limited reports on the influence of circadian rhythm on drug metabolism in culture. We observed the circadian rhythm in mouse embryonic stem (ES) cell-derived cardiomyocytes, as well as in the animal, after forskolin stimulation. The clock-synchronized mouse ES cell-derived cardiomyocytes exhibited time-dependent drug responses. This synchronized circadian rhythm could be maintained for up to three days by forskolin stimulation after every 24 hr. The beating rates of mouse ES cell-derived cardiomyocytes followed a circadian pattern. In conclusion, we established a mouse ES cell-derived cardiomyocyte culture model that exhibited a circadian beating pattern and time-dependent drug responses for up to three days. This model would serve as a valuable tool for chronotherapeutic research in culture.