Clinical chronopharmacology: the importance of time in drug treatment.

Nearly all functions of the body, including those influencing pharmacokinetic parameters such as drug absorption and distribution, drug metabolism and renal elimination, show significant daily variations: these include liver metabolism, hepatic blood flow and the first-pass effect; glomerular filtration, renal plasma flow and urine volume and pH; blood pressure, heart rate and organ perfusion rates; acid secretion in the gastro-intestinal tract and gastric emptying time. The onset and symptoms of diseases such as asthma attacks, coronary infarction, angina pectoris, stroke and ventricular tachycardia are circadian phase dependent. In humans, variations during the 24 h day in pharmacokinetics (chrono-pharmacokinetics) have been shown for cardiovascularly active drugs (propranolol, nifedipine, verapamil, enalapril, isosorbide 5-mononitrate and digoxin), anti-asthmatics (theophylline and terbutaline), anticancer drugs, psychotropics, analgesics, local anaesthetics and antibiotics, to mention but a few. Even more drugs have been shown to display significant variations in their effects throughout the day (chronopharmacodynamics and chronotoxicology) even after chronic application or constant infusion. Moreover, there is clear evidence that even dose/concentration-response relationships can be significantly modified by the time of day. Thus, circadian time has to be taken into account as an important variable influencing a drug's pharmacokinetics and its effects or side-effects.