PT  - JOURNAL ARTICLE
AU  - Danyi Lu
AU  - Mengjing Zhao
AU  - Min Chen
AU  - Baojian Wu
TI  - Circadian clock-controlled drug metabolism: Implications for chronotherapeutics
AID  - 10.1124/dmd.120.090472
DP  - 2020 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.120.090472
4099  - http://dmd.aspetjournals.org/content/early/2020/02/28/dmd.120.090472.short
4100  - http://dmd.aspetjournals.org/content/early/2020/02/28/dmd.120.090472.full
AB  - Dependence of drug metabolism on dosing time has been long recognized. However, it is until recent years that the underlying mechanisms for circadian metabolism are being clarified. Diurnal rhythmicity in expression of drug-metabolizing enzymes is believed to be a key factor determining circadian metabolism. Supporting the general notion that biological rhythms are generated and maintained by the circadian clock, a number of diurnal enzymes are under the control of circadian clock. In general, circadian clock genes generate and regulate diurnal rhythmicity in drug enzymes via transcriptional actions on one or two of three cis-elements (i.e., E-box, D-box, and RevRE or RORE). Additionally, cycling or clock-controlled nuclear receptors such as Hnf4α and Ppar-γ are contributors to diurnal enzyme expression. These newly discovered mechanisms for each of rhythmic enzymes are reviewed in this article. We also discuss how the rhythms of enzymes are translated to circadian pharmacokinetics and drug chronotoxicity that has direct implications for chronotherapeutics. Our discussion is also extended to two diurnal transporters (P-gp and Mrp2) that have an important role in drug absorption. Although the experimental evidence is lacking in metabolism-based chronoefficacy, circadian genes (e.g., Rev-erbα) as drug targets are shown to account for diurnal variability in drug efficacy.SIGNIFICANCE STATEMENT Significant progresses have been made in clarifying the molecular mechanisms for generation of diurnally rhythmicity in drug-metabolizing enzymes. In this article, we review the newly discovered mechanisms for each of rhythmic enzymes, and discuss how the rhythms of enzymes are translated to circadian pharmacokinetics and drug chronotoxicity that has direct implications for chronotherapeutics.