Are pigs a suitable animal model for in vivo metabolism studies of new psychoactive substances? A comparison study using different in vitro/in vivo tools and U-47700 as model drug. (1st September 2020)

• Record Type: Journal Article
• Authors: Nordmeier, Frederike; Doerr, Adrian; Laschke, Matthias W.; Menger, Michael D.; Schmidt, Peter H.; Schaefer, Nadine; Meyer, Markus R.
• Is Part Of: Toxicology letters. Volume 329(2020)
• Page Start: 12
• Page End: 19
• Publication Date: 2020-09-01
• Subjects: New synthetic opioids -- U-47700 -- Pigs -- Urinary metabolic patterns -- LC-HR-MS/MS; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2020.04.001
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: In vitro and in vivo metabolism studies of the new synthetic opioid U-47700 were elucidated using LC-HR-MS/MS. The pig urinary metabolic pattern was compared to different metabolizing systems (human and pig liver microsomes, human liver S9 fraction, rat) and to human data. In total, 12 phase I and 8 phase II metabolites were identified. Main metabolic reactions were N -demethylation and hydroxylation predominantly catalyzed by CYP2B6, CYP2C19, CYP3A4, and CYP3A5. Highlights: First study on metabolism of U-47700 in pigs in comparison to other tools. N-demethylation, hydroxylation, and combination of them followed by glucuronidation or sulfation as main metabolic reactions. Good correlation between pig and human metabolic patterns. Pigs are useful for elucidation of human metabolism and further toxicokinetic data of U-47700. Abstract: Being highly potent, New Synthetic Opioids (NSO) have become a public health concern. Little is known though about the metabolism and toxicokinetics (TK) of many of the non fentanyl NSO such as U-47700. Obtaining such data in humans is challenging and so we investigated if pigs were a suitable model species as TK model for U-47700. The metabolic fate of U-47700 was elucidated after intravenous administration to one pig in vivo and results were compared to metabolic patterns formed by different other in vitro systems (human and pig liver microsomes, human liver S9 fraction) and compared to rat and human in vivo data. Furthermore, monooxygenase isozymes responsible for the major metabolic steps were elucidated. In total, 12 phase I and 8 phase II metabolites of U-47700 could be identified. The predominant reactions were N -demethylation, hydroxylation, and combination of them followed by glucuronidation or sulfation. The most predominant monooxygenase catalyzed conversions were N -demethylation, and hydroxylation by CYP3A4 and 2B6, and FMO3 catalyzed N -oxidation. Similar main phase I metabolites were found in vitro as compared to in vivo (pig/human). The metabolic pattern elucidated in the pig was comparable to human in vivo data. Thus, pigs seem to be a suitable animal model for metabolism and further TK of U-47700.