Pharmacokinetic Studies of Flunitrazepam in Healthy Male Japanese Subjects

Abstract

Blood level profiles of flunitrazepam and its N-desmethyl-metabolite were investigated after single and multiple administrations of flunitrazepam to groups of 5 healthy male adult volunteers. Urinary excretion of some major metabolites of flunitrazepam was also examined following oral doses of a single 4 mg. Following the oral administration, the absorption of flunitrazepam was fairly rapid: the peak times were attained within 1–2 hr with peak levels of 9.6–16.0ng/ml for 2 mg dose and 20.6–30.3ng/ml for 4 mg dose. The drug then disappeared from the blood biphasically. The rate of disappearance was independent of the doses, while the AUC for the unaltered drug was dose-related. Blood levels of N-desmethyl flunitrazepam were always lower than those of the unaltered drug. 7-Amino-flunitrazepam and 3-hydroxy-flunitrazepam were major urinary metabolites, comprising about 9% and 5% of the dose, respectively, in the initial 72-hr urine. During repeated administration of the drug at a daily oral dose of 2 mg, the blood level profiles showed gradual elevation during the first few days, and then the steady-state was attained within 3–5 days. After i. v. injection of 2 mg, flunitrazepam was eliminated from the blood triphasically. The mean AUC for the unaltered drug obtained after the i. v. injection was about twice as much as that obtained after the oral administration of the identical dose. © 1978, The Japanese Society of Clinical Pharmacology and Therapeutics. All rights reserved.