The influence of circadian rhythms on the kinetics of drugs in humans

In clinical practice, it is important to consider circadian rhythms in pharmacokinetics and cell responses to therapy in order to design proper protocols for drug administration. Scientists have arrived at this conclusion after several experiments in animals and in humans have clearly demonstrated that all organisms are highly organised according to circadian rhythms. These temporal cycles influence different physiological functions and, consequently, can influence the pharmacokinetic phases of drugs. A drug's pharmacokinetics can be modified according to the time of drug administration. In fact, the circadian changes of > 100 different compounds have been documented. The results obtained have led several scientific societies to provide guidelines concerning the timing of drug dosing for anticancer, cardiovascular, respiratory, anti-ulcer, anti-inflammatory, immunosuppressive and antiepileptic drugs. Absorption may be influenced by circadian rhythms and most lipophilic drugs seem to be absorbed faster when the drug is taken in the morning compared with the evening; for water-soluble compounds, no circadian variation in the absorption of drugs has been found. Concerning drug distribution, the higher the blood flow fraction an organ receives, the higher the rate constant for transferring drugs out of the capillaries. This drug pharmacokinetic phase may be influenced by circadian variations in the protein binding of acidic and basic drugs. Drug metabolism may be influenced by daily modifications of blood flow. For drugs with a high extraction ratio, metabolism depends on hepatic blood flow, while that of drugs with a low extraction ratio depends on liver enzyme activity. Hepatic blood flow has been shown to be greatest at 8 am and metabolism seems to be reduced during the night. Finally, concerning drug elimination, the clearance of 'flow-limited' drugs that present a high extraction rate is affected by the blood flow delivered to the organ, independent of the cardiac output fraction supplied. Chronopharmacokinetics can explain individual differences in drug levels revealed by therapeutic drug monitoring and can be used to optimise the management of patients receiving drug therapy.