Title:
Chrono-pharmacokinetics; circadian clock regulation of drug disposition

 

Satoru Koyanagi
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University

Abstract:
Many biological processes are subject to daily oscillations, and some of these are controlled by self-sustained oscillation mechanism called “circadian clock”. This machinery operates at cellular level and coordinates a variety of physiological functions. The circadian rhythm in physiological functions also affects the efficacy and/or toxicity of drugs: the potency of a large number of drugs varies depending on their administration times.
In mammals, the circadian clock system is hierarchically organized, consisting of the light-responsive central clock in the suprachiasmatic nuclei (SCN) of hypothalamus and the subsidiary clocks in other brain region and peripheral tissues. The SCN are entrained to the environmental light-dark cycle and then synchronizes the subsidiary clocks, whereas the peripheral clocks regulate circadian rhythms in tissue-specific functions. Both central and peripheral clocks are governed by inter-connected transcriptional and translational feedback loops. The inter-connected loops consist of clock genes, and regulate circadian rhythms in output physiology through the periodic activation/repression of clock-controlled output genes. Recent studies in laboratory rodents have revealed that the circadian-controlled output pathways include regulatory factors responsible for the expression of xenobiotic transporters and drug metabolism enzymes. It is, however, difficult to predict the circadian change in the drug pharmacokinetics in a diurnally active human by using the data collected from nocturnally active rodents. Therefore, we used cynomolgus monkeys, diurnally active animal, to evaluate the circadian rhythmicity in the expression of genes affecting drug disposition.
In this seminar, I would like to summarize our findings on the molecular mechanism for circadian regulation of xenobiotic transporters and drug metabolism enzymes, and also to introduce the difference in the mechanism of circadian regulation of drug disposition between diurnally and nocturnally active animals.

 

References:
Iwasaki M, Koyanagi S, Suzuki N, Katamune C, Matsunaga N, Watanabe N, Takahashi M, Izumi T, Ohdo S; Circadian modulation in the intestinal absorption of p-glycoprotein substrates in monkeys. Mol Pharmacol 88: 29-37, 2015.

Murakami Y, Higashi Y, Matsunaga N, Koyanagi S, Ohdo S; Circadian clock-controlled intestinal expression of the multidrug-resistance gene mdr1a in mice. Gastroenterology 135: 1636-1644, 2008.