Circadian stage-dependent changes in diazepam kinetics

Area of Science:

• Pharmacokinetics
• Chronopharmacology

Background:

• Understanding diurnal variations in drug kinetics is crucial for optimizing therapeutic outcomes.
• Diazepam pharmacokinetics can be influenced by various factors, including administration time.

Purpose of the Study:

• To investigate the effect of dosing time (morning vs. evening) on diazepam kinetics in healthy men.
• To examine the influence of postprandial state versus fasting on time-dependent diazepam absorption and distribution.

Main Methods:

• 28 healthy male participants received 5-mg oral or intravenous diazepam doses.
• Dosing occurred in the morning or evening under fed or fasted conditions.
• Plasma concentrations, elimination half-life (t1/2), and area under the curve (AUC) were measured.

Main Results:

• Oral diazepam showed faster absorption and higher peak concentrations in the morning under fed conditions.
• Intravenous diazepam exhibited time-dependent kinetic changes, particularly when fasted.
• Lower diazepam free fraction in the morning correlated with higher total plasma concentrations.

Conclusions:

• Diurnal variations in diazepam kinetics are influenced by both absorption and distribution.
• Altered protein binding and gastrointestinal absorption contribute to time-dependent changes in diazepam pharmacokinetics.
• Dosing time and meal status significantly impact diazepam's pharmacokinetic profile.