Time-dependence in benzodiazepine pharmacokinetics. Mechanisms and clinical significance

Several studies investigating changes with time in pharmacokinetic parameters of several benzodiazepines are reviewed. At least 3 possibilities (enzyme induction, enzyme inhibition by metabolic products, and unchanged kinetics following long term therapy or high doses) have been postulated in the disposition processes of diazepam. It seems likely that the contradictory results which have been reported can be explained by differences in 1 or several experimental factors influencing the outcome of a study (patient compliance, multiple drug therapy or statistical design). With the 3-hydroxybenzodiazepine lorazepam and the nitro-benzodiazepine nitrazepam, no changes in metabolic activity were observed. Studies with clonazepam in monkeys have confirmed previous observations that reduced metabolic activity during periods of physical inactivity gives rise to circadian fluctuations in steady-state concentrations of the drug. Furthermore, systemic and intrinsic clearances of midazolam were found to be higher following an intravenous dose in the late afternoon than after a morning dose. The protein binding of diazepam is also subject to diurnal variations, and concomitant changes in apparent volume of distribution and clearance have been observed. From the existing data it seems likely that the rate of absorption of several benzodiazepines (including diazepam, clobazam and clorazepate) varies periodically with a 24-hour cycle, pointing to diurnal effects on drug absorption processes.