Plasma Diazepam Concentrations Following Prolonged Administration

Abstract

Plasma diazepam and N-desmethyl diazepam concentrations were measured in patients receiving diazepam 5 mg or 10 mg i.v. at 4-h intervals for periods of 6-22 days. At both doses there was an accumulation of both diazepam and its metabolite, the latter reaching concentrations of up to two to three times that of the parent drug. Plasma diazepam concentrations reached a plateau after 8 days while the concentration of N-desmethyl metabolite continued to increase throughtout the period of drug administration. On discontinuation of diazepam therapy both diazepam and N-desmethyl diazepam concentrations decreased slowly, the former with a half-life of 2-4 days and the latter with a half-life of 4-8 days.

Benzodiazepine Dependence

“…Tolerance to the sedative effects can be demonstrated in animals as the depression of exploratory and general motor activity induced by benzodiazepines wears off after a few days [80]. Most patients reporting initial drowsiness find it wanes over a few days [18,82,83,84]. Normal subjects given a single dose ofa long acting benzodiazepine such as clorazepate report progressively fewer subjective effects of drowsiness over the next few hours despite plasma concentrations of the drug hardly diminishing [85].…”

Comparative Study of Drug Interactions in Benzodiazepine Associated Deaths

“…The protein binding of diazepam is around 98.5% and the bioavailability is about 40-100% of oral administered dose [1]. Long-term therapy with diazepam leads steady state plasma concentrations of diazepam of 100-800 ng/mL [20,21]. Diazepam is primarily metabolized by CYP2C19 and CYP3A4 to the major active metabolite, nordazepam.…”