Time-of-day Effect of Intravenous Diazepam on Pharmacologic Actions in Man

Abstract

Our group previously reported the time-of-day effect of oral administration on diazepam kinetics and its sedative action in healthy men. In these studies, it has been suggested that the absorption rate of diazempam from the gastrointestinal tract is faster in morning dosing than in evening dosing. The present study was performed to elucidate the mechanism of time-of-day effect on diazepam kinetics and dynamics, administering 5 mg diazepam (Cercine® injectable solution) intravenously under the same experimental conditions as the oral dose study described above. Eight healthy volunteers participated in the study. The subjects received a 5-mg dose of diazepam intravenously at 9: 30 a. m. and after a 2-wk interval, at 9: 30 p.m., in a randomly assigned cross-over study. Meals were standardized in order to fit the subjects' usual meal amount. Plasma diazempam concentrations were determined by gas chromatography (ECD). Changes in subjective feelings such as “mentally slow”, “feeble”, “clumsy”, and “lethargic” were more marked in the morning trial at 0.5 hr after injection. More marked sedative effects were demonstrated in the morning trial by using the digit symbol substitutiontest and the continuous number addition test. Mean (±SD) total diazepam concentrations in plasma in the morning trial vs in the evening trial were: 218 (±15) vs 192 (±12) ng/ml at 0.5 hr after drug administration (0.05<P<0.1); 164 (±39) vs 132 (±16) ng/ml at 1 hr after injection (P<0.05). The results suggest that there exists time-of-day effect of intravenous injection with diazepam injectable solution onsedative actions and kinetics, which may be clinically important in some situations. Inaddition, the time-dependent kinetics of diazepam after oral dosing cannot be explainedonly by the absorption rate from the gastrointestinal tract, since intravenousadministration of diazepam did not eliminate the difference in total plasma diazepamconcentrations between morning and evening dosing at 0.5 hr and 1 hr after injection.