In vitro glucuronidation of designer benzodiazepines by human UDP-glucuronyltransferases
| Autor: | Markus R. Meyer, Hans H. Maurer, Lea Wagmann, Madeleine Pettersson Bergstrand, Lilian H.J. Richter |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
UGT1A4
Insecta Glucuronidation Pharmaceutical Science 01 natural sciences Analytical Chemistry Designer Drugs 03 medical and health sciences Benzodiazepines 0302 clinical medicine Glucuronides Tandem Mass Spectrometry Microsomes medicine Clonazolam Environmental Chemistry Animals Humans 030216 legal & forensic medicine Glucuronosyltransferase Spectroscopy Chemistry 010401 analytical chemistry 0104 chemical sciences Substance Abuse Detection Deschloroetizolam dBZ Biochemistry Flubromazolam Etizolam Glucuronide medicine.drug Chromatography Liquid |
| Zdroj: | Drug testing and analysis. 11(1) |
| ISSN: | 1942-7611 |
| Popis: | Multiple new psychoactive substances (NPS) are released into the recreational drug market each year. One NPS drug class that has become more common in recent years is that of the benzodiazepines (designer benzodiazepines, DBZ). Several metabolism studies have been performed to improve their bioanalytical detection via the best target. These studies have shown the presence of parent glucuronides and, as polymorphisms have been noted for the catalyzing enzymes (UDP-glucuronyltransferases) responsible for glucuronide conjugation reactions, it is important to keep this in mind when interpreting DBZ cases in clinical and/or forensic toxicology. Therefore, the aim of this study was to determine the UDP-glucuronyltransferases (UGTs) responsible for parent compound conjugation of nine DBZ to facilitate interpretation of related cases. Clonazolam, deschloroetizolam, etizolam, flubromazolam, flunitrazolam, metizolam, nifoxipam, nitrazolam, and pyrazolam were incubated with pooled human liver microsomes (pHLM) or 13 different human UGTs. The samples were analyzed using liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS). Glucuronide conjugates of flunitrazolam and nifoxipam were only detected in pHLM, suggesting that these reactions are performed by dimer complexes of several UGTs or complexes between UGTs and other metabolizing enzymes contained in pHLM. Nitrazolam or pyrazolam glucuronides were not detected. Glucuronidation of clonazolam, deschloroetizolam, etizolam, flubromazolam, and metizolam was catalyzed exclusively by UGT1A4. The conjugation of the majority of the DBZ was performed by the UGT isoform 1A4 for which polymorphisms have been described. This underlines the importance of taking glucuronidation polymorphism into consideration when interpreting intoxication cases. |
| Databáze: | OpenAIRE |
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