Chronopharmacokinetics. Current status.

Absorption, distribution, metabolism and elimination are influenced by many different physiological functions of the body which may vary with time of day. Thus, the pharmacokinetic parameters characterising these different steps, conventionally considered to be constant in time, depend on the moment of drug administration. Time of day has to be regarded as an additional variable influencing the kinetics of a drug. Chronokinetic studies have been reported for many drugs in an attempt to explain chronopharmacodynamic phenomena and demonstrate that the time of administration is a possible factor of variation in the kinetics of a drug. In this paper this is illustrated with the chronopharmacokinetics of cardiovascular and nonsteroidal anti-inflammatory drugs. Time-dependent changes in kinetics may proceed from circadian variations at each step, e.g. absorption, distribution, metabolism and elimination. Thus, circadian variations in gastric acid secretion and pH, motility, gastric emptying time, gastrointestinal blood flow, drug protein binding, liver enzyme activity and/or hepatic blood flow, glomerular filtration, renal blood flow, urinary pH and tubular resorption may play a role in such kinetic variations. New tools, such as new formulation procedures or pumps with constant or programmable delivery rates, now make it possible to deliver a drug at a definite time, or during a definite span of time and at a controlled rate in chronokinetic studies. Microdialysis would be of particular interest in chronopharmacological and chronokinetics studies, but, surprisingly, very few chronobiological studies have been conducted using this technique. With regard to new models and concepts in chronokinetics, pharmacokinetic-pharmacodynamic modelling may be useful, and modelling of the chronopharmacological patterns of drug response and kinetics have been attempted by some authors. Drug chronopharmacokinetic knowledge may be clinically relevant as it may have implications for drug prescription by modulating the distribution of the total daily dose along the 24-hour scale. However, it seems reasonable to consider chronopharmacokinetic studies in specific cases related to patients, illness or the drug itself. When conducting a chronokinetic study it is not only necessary to take into account differences in the time of administration but to also have strict control of all other possible variables which are known to influence pharmacokinetic processes.