Figure 5.

REV‑ERBα is involved in chronopharmacokinetics and chronotoxicity via regulating drug-metabolizing enzymes (DMEs). REV-ERBα directly or indirectly regulates clock-controlled genes (CCGs) involved in drug metabolism. The DMEs consists of “phase I enzymes” and “phase II enzymes”. Circadian expressions of these genes result in dosing time-dependent pharmacokinetics and therefore in time-varying drug effects (toxicity and efficacy). For instance, Cyp2b10 (a Rev-erbα target) metabolizes cyclophosphamide (CPA) to its toxic (4-hydroxylated) metabolite 4-OH-CPA. The CPA chronotoxicity is associated with time-varying generation of 4-OH-CPA caused by diurnal Cyp2b10 expression.