Chronopharmacology and its application to the development of theophylline treatment schedules for asthma.

Abstract

asthma, chronopharmacology, theo- phylline; circadian rhythms, pharmacokinetics Pharmacokinetic variables, such as area under the curve (AUC), mean residence time (MRT), peak concentration (Cmax), time to the peak (tmax), and elimination half-life (tl/2) are nearly always re- ported with the underlying assumption that the kinetics are time-invariant. However, many biologi- cal rhythms can be detected in all animal species, and there is a good deal of published evidence of circadian, circannual, and other rhythmic changes in the responses of organisms to a large variety of physical and chemical agents. In turn, this has led to a substantial literature describing rhythmic changes in plasma drug concentrations (chrono- pharmacokinetics) and in drug effects (chronophar- macodynamics). In a 1982 paper, Reinberg and Smolensky [1] re- viewed the published evidence of circadian changes in drug disposition for four groups of drugs: - 1)Analgesic and nonsteroidal anti-inflammatory drugs, including sodium salicylate, aspirin, indo- methacin, paracetamol, phenacetin, and amido- pyrine. 2) Theophylline, digitalis, and propranolol. 3)Drugs used in neurology and psychiatry, in- cluding dipotassium chlorazepate, hexobarbitone, lithium carbonate, phenytoin, and nortriptyline. 4)Antibacterial, anticancer, and other agents, in- cluding erythromycin, ampicillin, cisplatin, d- xylose, ferrous sulphate, and potassium chloride. The chronopharmacokinetic effects listed included variations in AUC, Cmax, tmax, the terminal elimina- tion rate in plasma, and the urinary elimination rate. An example, drawn from [2], illustrating the chrono- pharmacokinetics of indomethacin, is shown in Fig. 1. In 1986 Lemmer [3] reviewed the chronophar- macology of cardiovascular drugs and listed evi- dence from 22published papers of circadian changes in pharmacodynamics, the effects includ- ing changes in blood pressure, heart rate, and elec- trocardiographic features.