Perimortem Distribution of U-47700, Tramadol and Their Main Metabolites in Pigs Following Intravenous Administration

Abstract

In spite of a decreasing number of new releases, New Synthetic Opioids (NSO) are gaining increasing importance in postmortem (PM) forensic toxicology. For the interpretation of analytical results, toxicokinetic (TK) data, e.g. on tissue distribution, are helpful. Concerning NSO, such data are usually not available due to the lack of controlled human studies. Hence, a controlled TK study using pigs was carried out and the tissue distribution of U-47700 and tramadol as reference was examined. Twelve pigs received an intravenous dose of 100 µg/kg body weight (BW) U-47700 or 1000 µg/kg BW tramadol, respectively. Eight hours after administration, the animals were put to death with T61. Relevant organs, body fluids and tissues were sampled. After homogenization and solid-phase extraction, quantification was performed applying standard addition and liquid chromatography-tandem mass spectrometry. At the time of death, the two parent compounds were determined in all analyzed specimens. Regarding U-47700, concentrations were highest in duodenum content, bile fluid and adipose tissue (AT). Concerning tramadol, next to bile fluid and duodenum content, highest concentrations were determined in the lung. Regarding the metabolites, N-desmethyl-U-47700 and O-desmethyltramadol (ODT) were detected in all analyzed specimens except for AT (ODT). Higher metabolite concentrations were found in specimens involved in metabolism. N-desmethyl-U-47700 showed much higher concentrations in routinely analyzed organs (lung, liver, kidney) than U-47700. To conclude, besides the routinely analyzed specimens in PM toxicology, AT, bile fluid and duodenum content could serve as alternative matrices for blood, urine or standard specimens such as kidney or liver. In case of U-47700, quantification of the main metabolite N-desmethyl-U-47700 is highly recommendable.

Toxicokinetics of U-47700, tramadol, and their main metabolites in pigs following intravenous administration: is a multiple species allometric scaling approach useful for the extrapolation of toxicokinetic parameters to humans?

“…Hence, total doses of 4.2 ± 0.1 mg of U-47700 and 42.8 ± 2.1 mg of tramadol were reached. As already described in a previous study (Nordmeier et al 2021), the tramadol dose was similar to common human therapeutic i.v. dosages (Gelbe Liste 2020).…”

“…The preparation of the used buffer and drug-free pig blood samples as well as the preparation of stock solutions, calibration standards, and quality control samples was performed according to a previously published study (Nordmeier et al 2021 ). The preparations are described in detail in the ESM (S1).…”

“…SPE was carried out according to a previous study (Nordmeier et al 2021 ) and is described in detail in the ESM (S1).…”

“…The LC–MS/MS conditions were already described in a previous study (Nordmeier et al 2021 ) and are provided in detail in the ESM (S1).…”

“…As already described in previous studies (Schaefer et al 2016 , 2017 , 2018 ; Nordmeier et al 2020a , 2021 ), the experiments were carried out according to the German legislation on protection of animals and the National Institute of Health Guide for the Care and Use of Laboratory Animals (Permission no: 32/2018). For this TK study, 12 domestic male pigs (Swabian Hall strain, mean body weight (BW) 42.8 ± 1.9 kg) were used.…”