Chronopharmacology: new insights and therapeutic implications

Abstract

Most facets of mammalian physiology and behavior vary according to time of day, thanks to endogenous circadian clocks. Therefore, it is not surprising that many aspects of pharmacology and toxicology also oscillate according to the same 24-h clocks. Daily oscillations in abundance of proteins necessary for either drug absorption or metabolism result in circadian pharmacokinetics, and oscillations in the physiological systems targeted by these drugs result in circadian pharmacodynamics. These clocks are present in most cells of the body, organized in a hierarchical fashion. Interestingly, some aspects of physiology and behavior are controlled directly via a "master clock" in the suprachiasmatic nuclei of the hypothalamus, whereas others are controlled by "slave" oscillators in separate brain regions or body tissues. Recent research shows that these clocks can respond to different cues and thereby show different phase relationships. Therefore, full prediction of chronopharmacology in pathological contexts will likely require a systems biology approach that considers chronointeractions among different clock-regulated systems.

Figure 1. The canonical mammalian circadian oscillator and output relevant for xenobiotic metabolism

Two interlocked feedback loops composed of activators (green) and repressors (red) that drive gene expression of output genes such as those important for xenobiotic metabolism. Components of these loops make extensive use of auxiliary factors including histone methyltransferases (HMTs), histone deacetylases (HDACs), DHBS family RNA-binding proteins (beige), and kinases and proteasome machinery (grey). Important output genes, involved in transcriptional control of the detoxification metabolism (blue). See text for details.

Figure 2. Modulation of drug pharmacokinetic by the circadian clock

All rhythmic parameters influencing drug transport and metabolism are highlighted in red. Characteristic functions of the circadian clock on these process are indicated in the respective organs.

Figure 3. Time of day dependent variation in pharmacokinetics.

Average 3-hourly steady state serum concentrations of theophylline from eight asthmatic children dosed with Theo24© before breakfast (06:00, red) or at bedtime (21:00, blue) as indicated by arrows. Shaded area represents the occurrence of dyspnea. (Adapted from Smolensky et al 1987 and Dethlefsen & Repges (1985) c.f. Smolensky et al. (1987))