Circadian rhythms in theophylline disposition: simulations and observations in the dog.
A constant-rate iv infusion of aminophylline approaching steady state in four dogs was used to investigate a circadian rhythm in theophylline disposition. A significant circadian rhythm (p less than 0.05, group cosinor analysis) was observed for serum theophylline concentrations and for the urinary excretion rates of theophylline and 3-methylxanthine. The phase relationship of the observed circadian rhythms in urinary pH to circadian changes in serum theophylline concentrations were supportive of a circadian rhythm in renal clearance of theophylline. Computer simulations indicated that circadian changes in serum theophylline concentration and urinary excretion of theophylline and its metabolites could be accounted for by a circadian rhythm in theophylline renal clearance and metabolism to 3-methylxanthine. A circadian rhythm in theophylline volume of distribution could not be totally dismissed as potentially having some effect on disposition. The timing of food intake is hypothesized to play a role in synchronizing the observed rhythm in serum theophylline concentrations.
Rackley
R J
RJ
Ciba-Geigy Corporation, Summit, NJ 07901.
Meyer
M C
MC
Straughn
A B
AB
D000818:Animals; D002940:Circadian Rhythm; D004285:Dogs; D005260:Female; D006863:Hydrogen-Ion Concentration; D013806:Theophylline / Q000493:pharmacokinetics*
D013806:Theophylline