Metabolic Profile of Flunitrazepam: Clinical and Forensic Toxicological Aspects

Background: Flunitrazepam (FNZ) is a potent hypnotic, sedative, and amnestic drug used to treat insomnia and as a pre-anesthetic agent. The illicit practice in drug-facilitated sexual assault led to important clinical and forensic concerns. Objective: In this work the metabolism of FNZ, and pharmacological- and toxicological-related effects, were fully reviewed. Methods: FNZ and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Results: Major metabolic pathways include N-demethylation, 3-hydroxylation, nitro-reduction, and further N-acetylation of the amino group, yielding N-desmethylflunitrazepam, 3-hydroxy-flunitrazepam, 7-aminoflunitrazepam, and 7-acetamidoflunitrazepam, respectively. A combination of these reactions may lead to the formation of 7-amino-N-desmethylflunitrazepam, 7-acetamido-N-desmethylflunitrazepam, 3- hydroxy-7-aminoflunitrazepam, 3-hydroxy-7-acetamidoflunitrazepam, 3-hydroxy-N-desmethylflunitrazepam and glucuronide conjugates. Genotypic variations in enzymes, interactions with other drugs or stability of FNZ during storage can result in large interindividual variability in the toxicological results. Conclusion: It is aimed that knowing the metabolism of FNZ may lead to the development of new analytical strategies for early detection, since this drug is typically present in very low concentrations in blood and urine when used to facilitate sexual assault. Keywords: Flunitrazepam, metabolism, pharmacokinetics, toxicological analysis, genotypic variations, sexual assault.