Circadian stage-dependent changes in diazepam kinetics.

The effect of dosing time on diazepam kinetics was investigated in 28 healthy men. A 5-mg dose of diazepam was given orally or intravenously on two occasions, in the morning (9:30 A.M.) or in the evening (9:30 P.M.) under the postprandial condition or after a 9-hr fast. After oral doses under postprandial conditions, the mean peak total diazepam concentration in plasma was higher and the time to peak concentration was faster after morning dosing than after evening dosing, but neither mean elimination t1/2 nor AUC between morning and evening dosings differ. Intravenous diazepam did not eliminate the time-dependent changes in diazepam kinetics occurring soon after injection under postprandial conditions, although it diminished the difference. During the 9-hr fast, time-dependent changes in diazepam kinetics were marked, especially after intravenous injection. Diazepam free fraction was lower 0.5 hr after intravenous dosing in the morning, and there was a negative correlation (r = -0.678) between the diazepam free fraction and total diazepam plasma concentration. These results suggest that diurnal variations in rate of drug distribution because of alterations in protein binding as well as in absorption from the gastrointestinal tract contribute to time-dependent changes in diazepam kinetics.