[Basic mechanisms of chronopharmacology]

Abstract

Many animal and human studies have demonstrated time-dependent changes in the effects and kinetics of drugs that can be explained in part by parallel changes in their absorption, metabolism and excretion. Although food influences drug absorption, its presence in the stomach does not explain the circadian rhythms in the absorption of xenobiotics. Circadian rhythms in blood flow, biliary secretion and the physico-chemical properties of drugs seem to be very important factors involved in the circadian rhythms of drug absorption. Time-dependent changes have been reported in the activity of hepatic enzyme involved in drug metabolism and they can explain the circadian rhythms in the effect of hexobarbital and in the kinetics of acetaminophen. However, circadian changes in blood flow, biliary secretion and in the binding to plasma proteins must be investigated thoroughly because they could explain many circadian rhythms in drug metabolism. The role of hepatic extraction ratio must also be looked at carefully. Finally, circadian changes in urinary pH, glomerular filtration and in other mechanisms of drug elimination by the kidneys can account for the circadian rhythms in the elimination of drugs such as the salicylates and furosemide. Future research on the molecular mechanisms of the circadian variations in the effects and kinetics of drugs must be carried out to give health professionals a better understanding of the phenomenon. Concepts and findings from investigative chronopharmacology are becoming now indispensable to solve problems of drug optimization.