Chronopharmacokinetics and development of drug delivery system

Many biological processes in mammals are subject to daily oscillations, and some of these are controlled by self-sustained oscillation mechanism called circadian clock. The rhythmic variations in biological functions also affect the efficacy and/or toxicity of drugs: the potency of a large number of drugs varies depending on the time of day when the drugs are administered. Circadian rhythms are controlled by a genetic feedback loops composed of clock genes. This mechanism interconnects the positive and negative limbs of circadian clockwork circuitry and also regulates 24-hr variation in output physiology through the periodic activation/repression of clock-controlled genes. The circadian-controlled output pathways include those that control the expression of many enzymes and regulators involved in xenobiotic detoxification, such as cytochrome P450 enzymes, carboxylesterases, and xenobiotic transporters. In addition to the intracellular molecular clock, circadian rhythms in cell physiology are also generated by extracellular factors. During the daily feeding cycle, the time-dependent accumulation of bile acids in the intestinal epithelial cells generates circadian changes in the expression of several types of transporter. This may also constitute a molecular clock-independent mechanism by which bile acid causes the circadian change in the intestinal absorption of drugs. This review presents an overview of regulation mechanism for circadian changes in the drug disposition and describes the importance of DDS development for rational chronopharmacotherapy.