Biological rhythms are endogenous and genetically-based. Circadian (about 24-hour) rhythms are coordinated in mammals by one or several biological clocks, including the suprachiasmatic nucleus. As a result, the bioavailability of a toxicant (toxicokinetics) as well as the susceptibility of target tissues to its actions are modulated along the 24-hour time scale. Large differences in toxic effects of numerous drugs have been documented, whatever the route of administration, after acute or chronic dosing and in several animal species and strains. Reduced glutathione content of tissues, cytochrome P-450 activities, and DNA synthesis represent a few of the intracellular targets for which a circadian change greater than 200% was demonstrated in laboratory rodents. Since the relevance of chronotoxicology experiments for oncologic drugs has now been validated in clinical phase I, II, and III trials, it is hoped that knowledge of the circadian time structure of living beings will guide a safer development of new chemical entities.
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