Diazepam is administered orally, rectally, and parenterally. Anticonvulsant, skeletal muscle relaxant, and anxiolytic effects are usually evident after the first dose. The duration for some clinical effects (e.g., sedation, anticonvulsant activity) is much shorter than would be expected considering the very long half-life for both diazepam and its metabolite, desmethyldiazepam.
Diazepam is widely distributed, with CSF levels similar to plasma levels. This benzodiazepine crosses the placenta and distributes into breast milk. The disparity between elimination half-life and duration of action for some conditions may be partially explained by rapid shifts in distribution of diazepam out of the CNS. Although diazepam is 99% protein-bound, interactions based on protein binding are not clinically significant. Metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4). Diazepam is extensively metabolized to one major active metabolite desmethyldiazepam and two minor active metabolites temazepam (3-hydroxydiazepam) and oxazepam (3-hydroxy-N-diazepam), with half-lives of 30—100 hours, 9.5—12 hours, and 5—15 hours, respectively. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam. Oxazepam and temazepam plasma concentrations are usually undetectable. The half-life of diazepam is 30—60 hours. These metabolites are subsequently glucuronidated and excreted in the urine.
