Toxicokinetic Studies and Analytical Toxicology of the New Synthetic Opioids Cyclopentanoyl-Fentanyl and Tetrahydrofuranoyl-Fentanyl
| Autor: | Matthias J Richter, Tanja M. Gampfer, Lea Wagmann, Svenja Fischmann, Folker Westphal, Markus R. Meyer |
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| Rok vydání: | 2020 |
| Předmět: |
Male
CYP2D6 Toxicodynamics Urinalysis Health Toxicology and Mutagenesis Urine Pharmacology Toxicology 01 natural sciences Designer Drugs Analytical Chemistry 03 medical and health sciences Cytochrome P-450 Enzyme System Tandem Mass Spectrometry Analytical Toxicology Cytochrome P-450 CYP3A medicine Animals Humans Environmental Chemistry Toxicokinetics 030304 developmental biology 0303 health sciences Chemical Health and Safety medicine.diagnostic_test CYP3A4 Chemistry 010401 analytical chemistry Rats 0104 chemical sciences Analgesics Opioid Fentanyl Cytochrome P-450 CYP2D6 Chromatography Liquid Protein Binding |
| Zdroj: | Journal of Analytical Toxicology. 44:449-460 |
| ISSN: | 1945-2403 0146-4760 |
| Popis: | The growing number of new synthetic opioids (NSO) on the new psychoactive substances (NPS) market bears new challenges in toxicology. As their toxicodynamics and particularly their toxicokinetics are usually unknown, impact on human health is not yet fully understood. Detection of the 2 NSO cyclopentanoyl-fentanyl (CP-F) and tetrahydrofuranoyl-fentanyl (THF-F) was first reported in 2016. Both were involved in several fatal intoxication cases, but no detailed information about their toxicological characteristics is available so far. The main purpose of this study was therefore to investigate the in vitro toxicokinetics and in vivo analytical toxicology of CP-F and THF-F by means of liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS). These studies included metabolic stability, phase I and II metabolism, isozyme mapping, plasma protein binding and detectability in LC-HRMS/MS standard urine screening approaches (SUSA) using rat urine samples. In total, 12 phase I metabolites of CP-F and 13 of THF-F were identified, among them 9 metabolites described for the first time. Overall, N-dealkylations, hydroxylations and dihydroxylations were the main metabolic reactions. The cytochrome P450 (CYP) isozymes mainly involved were CYP2D6 and CYP3A4, leading to elevated drug levels and intoxications in CYP2D6 poor metabolizers. CP-F showed a high plasma protein binding of 99%, which may increase the risk of toxicity by simultaneous intake of other highly bound drugs. Detectability studies showed that neither the parent compounds nor their metabolites were detectable in rat urine using LC-HRMS/MS SUSA. However, a more sophisticated analytical strategy was successfully applied and should be used for analytical confirmation of an intake of CP-F and/or THF-F. |
| Databáze: | OpenAIRE |
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