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Since both benzodiazepines and their metabolites can result from gidazepam metabolism, it is important to identify markers that specifically indicate consumption of each compound. We therefore investigated the human metabolism of gidazepam and desalkylgidazepam by incubating them with human hepatocytes and analyzing the resulting samples, along with human blood from a confirmed desalkylgidazepam-positive case, using liquid chromatography-high-resolution mass spectrometry. To further assess their pharmacological profile, we examined the activity of gidazepam, desalkylgidazepam, and their potential (3\n                    <jats:italic>R<\/jats:italic>\n                    )- and (3\n                    <jats:italic>S<\/jats:italic>\n                    )-hydroxy metabolites at \u03b3-aminobutyric acid A (GABA\n                    <jats:sub>A<\/jats:sub>\n                    R) and 18\u00a0kDa translocator protein (TSPO) receptors in silico, using AutoDock Tools and UCSF Chimera. Gidazepam was metabolized through\n                    <jats:italic>N<\/jats:italic>\n                    -desalkylation (yielding desalkylgidazepam),\n                    <jats:italic>N<\/jats:italic>\n                    -acetylation, and\n                    <jats:italic>N<\/jats:italic>\n                    -glucuronidation. Conversely, desalkylgidazepam was subjected to hydroxylation and subsequent\n                    <jats:italic>O<\/jats:italic>\n                    -glucuronidation reactions. Notably, gidazepam demonstrated a lower affinity at GABA\n                    <jats:sub>A<\/jats:sub>\n                    R\u2019s prominent \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    \/\u03b3\n                    <jats:sub>2<\/jats:sub>\n                    site compared to desalkylgidazepam and its (3\n                    <jats:italic>R<\/jats:italic>\n                    )- and (3\n                    <jats:italic>S<\/jats:italic>\n                    )-hydroxy metabolites. However, its interaction with the transmembrane domains of the \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    subunit may account for its anxiolytic effects. For the TSPO receptor, gidazepam and 3-hydroxy desalkylgidazepam metabolites showed higher binding affinity, whereas desalkylgidazepam did not bind to TSPO. Our findings suggest blood markers specific to gidazepam, namely gidazepam-\n                    <jats:italic>N<\/jats:italic>\n                    -glucuronide and\n                    <jats:italic>N<\/jats:italic>\n                    -acetyl gidazepam, are essential for confirming gidazepam consumption. In addition, in silico modelling supports the hypothesis that gidazepam functions as a prodrug via GABA\n                    <jats:sub>A<\/jats:sub>\n                    R and as an agonist at TSPO. Further research is necessary to clarify designer benzodiazepine activity at TSPO.\n                  <\/jats:p>","DOI":"10.1007\/s00204-025-04249-z","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T19:18:47Z","timestamp":1765221527000},"page":"959-978","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Insights into the human metabolism and in silico receptor activity of gidazepam and desalkylgidazepam"],"prefix":"10.1007","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3194-3250","authenticated-orcid":false,"given":"Prince Sellase","family":"Gameli","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8693-9312","authenticated-orcid":false,"given":"Johannes","family":"Kutzler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8034-8557","authenticated-orcid":false,"given":"Cristina","family":"Minnelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9602-4223","authenticated-orcid":false,"given":"Giuseppe","family":"Basile","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8053-6539","authenticated-orcid":false,"given":"Emiliano","family":"Laudadio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3082-4532","authenticated-orcid":false,"given":"Francesco Paolo","family":"Busard\u00f2","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1883-2804","authenticated-orcid":false,"given":"Volker","family":"Auw\u00e4rter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-9518","authenticated-orcid":false,"given":"Jeremy","family":"Carlier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"4249_CR1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.14412\/2074-2711-2024-5-91-98","volume":"16","author":"YE Azimova","year":"2024","unstructured":"Azimova YE, Petelin DS (2024) Gidazepam \u2013 daytime tranquilizer for the treatment of anxiety. 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