Identification of Circadian Determinants of XXXX Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling.

@entity1 @entity137 @entity2600 @entity5 @entity19 @entity8713 @entity14
@entity5 chronotherapy aims at enhancing tolerability and efficacy of anticancer drugs through their delivery according to circadian clocks. However, @entity19 and @entity1 data show that lifestyle, sex, genetics, drugs, and @entity5 can modify both host circadian clocks and metabolism pathways dynamics, and thus the optimal timing of drug administration. The mathematical modeling of chronopharmacology could indeed help moderate optimal timing according to @entity1 -specific determinants. Here, we combine in vitro and in silico methods, in order to characterize the critical molecular pathways that drive the chronopharmacology of @entity2600 , a topoisomerase I inhibitor with complex metabolism and known activity against @entity14 . Large transcription rhythms moderated drug bioactivation, detoxification, transport, and target in synchronized @entity14 . These molecular rhythms translated into statistically significant changes in pharmacokinetics and pharmacodynamics according to in vitro circadian drug timing. The top-up of the multiple coordinated chronopharmacology pathways resulted in a four-fold difference in @entity2600 -induced apoptosis according to drug timing. @entity2600 @entity137 was directly linked to clock gene @entity8713 expression: The least apoptosis resulted from drug exposure near @entity8713 mRNA nadir (P < 0.001), whereas clock silencing through siBMAL1 exposure ablated all the chronopharmacology mechanisms. Mathematical modeling highlighted circadian bioactivation and detoxification as the most critical determinants of @entity2600 chronopharmacology. In vitro-in silico systems chronopharmacology is a new powerful methodology for identifying the main mechanisms at work in order to optimize circadian drug delivery.
