Influence of morning or evening administration on absorption of theophylline.
BACKGROUND
Bronchoconstriction during the night causing nocturnal and early morning wheezing is recognized as a major problem for asthmatics. Oral sustained-release theophyllines (SRTs) were developed to reduce the symptoms. A circadian variation in theophylline kinetics has been demonstrated with many SRTs. The purpose of this study was to evaluate the differences in serum theophylline concentration (STC) caused by morning or evening dosing of Euphyllin Retard, a brand of SRT, for a period of 36 hours following oral administration.


METHODS
A total of nine non-smoking healthy male volunteers were involved in the study, with a two-period crossover comparison. They were randomly divided into two groups. The first group took a single oral dose of 350 mg Euphyllin Retard at 8:00 A.M. and the second group took it at 8:00 P.M. Blood samples were collected during the 36 hours following administration. Two weeks later, the first group took the drug at night and the second group took it in the morning. The difference in the absorption of theophylline with daytime administration versus night-time administration was assessed using pharmacokinetic parameters derived from the plasma drug concentration vs time curve.


RESULTS
The means of unextrapolated area under the concentration vs time curve (AUC) from time 0 to 24 hours (AUCUN) and of the extrapolated AUC from time 0 to infinity (AUCEX) in the night phase were higher than those in the day phase (62.403 micrograms/ml/hr vs 53.081 micrograms/ml/hr, p = 0.9186; 107.21 micrograms/ml/hr vs 98.879 micrograms/ml/hr, p = 0.8807, respectively). The mean of maximum concentration (Cmax) was higher in the night phase than that in the day phase (4.166 micrograms/dl vs 3.451 micrograms/dl, p = 0.9234). Daytime administration showed a delayed time to maximum concentration (Tmax) when compared to that of night-time administration (6.5 hr vs 5.75 hr, p = 0.6244). The terminal elimination rate constant (Kel) was lower in the day phase than in the night phase (0.053 l/hr vs 0.06 l/hr, p = 0.7601). The day phase and night phase data are combined data from the two night and two day groups. The statistical analysis of the results show that the time of administration does not influence the STC.


CONCLUSIONS
No diurnal variation in theophylline kinetics was found with Euphyllin Retard. This study was performed in a limited number of normal healthy subjects, and the same result is yet to be proved in asthmatic patients and a larger population of normal subjects.
Su
Y M
YM
Department of Internal Medicine, Far Eastern Memorial Hospital, Pan-Chiao, Taipei, Taiwan, ROC.
Cheng
T P
TP
Yeh
T W
TW
Wen
C Y
CY
Wang
D I
DI
D000042:Absorption; D000293:Adolescent; D000328:Adult; D001993:Bronchodilator Agents / Q000493:pharmacokinetics*; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D006801:Humans; D008297:Male; D013806:Theophylline / Q000008:administration & dosage / Q000493:pharmacokinetics*
D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; D013806:Theophylline