Time-dependence in Diazepam Kinetics after Repeated Doses in Man

The time-dependence in diazepam kinetics after a single oral dose and after repeated oral doses was investigated in 5 healthy volunteers. Subjects took a single oral 5 mg dose of diazepam on two occasions, in the morning (09: 30) or in the evening (21: 30). Then they took repeated oral 5 mg doses once a day for 8 days every morning or every evening. After repeated oral doses as well as after a single oral dose, the mean peak total diazepam concentration in plasma (C_max) tended to be higher in the morning trial. However, no difference was found in the mean elimination half-life, (t_1/2), the area under the plasma concentration time-curve (AUC), the volume of distribution (Vd), or the total plasma clearance (CL) after repeated diazepam doses between morning and evening. The results found in the single dose study were essentially identical to the findings reported previously by our group. The time-dependence in diazepam kinetics was also found after repeated administrations. The mechanism of this time-dependency in the drug seems to be explained by the time-dependent variations in the rate of absorption from the gastrointestinal tract and the rate of distribution of the drug. The plasma diazepam clearance significantly increased after repeated doses.