Metabolic patterns of JWH‐210, RCS‐4, and THC in pig urine elucidated using LC‐HR‐MS/MS: Do they reflect patterns in humans?

Abstract

The knowledge of pharmacokinetic (PK) properties of synthetic cannabinoids (SCs) is important for interpretation of analytical results found for example in intoxicated individuals. In the absence of human data from controlled studies, animal models elucidating SC PK have to be established. Pigs providing large biofluid sample volumes were tested for prediction of human PK data. In this context, the metabolic fate of two model SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4), was elucidated in addition to Δ -tetrahydrocannabinol (THC). After intravenous administration of the compounds, hourly collected pig urine was analyzed by liquid chromatography-high resolution mass spectrometry. The following pathways were observed: for JWH-210, hydroxylation at the ethyl side chain or pentyl chain and combinations of them followed by glucuronidation; for RCS-4, hydroxylation at the methoxyphenyl moiety or pentyl chain followed by glucuronidation as well as O-demethylation followed by glucuronidation or sulfation; for THC, THC glucuronidation, 11-hydroxylation, followed by carboxylation and glucuronidation. For both SCs, parent compounds could not be detected in urine in contrast to THC. These results were consistent with those obtained from human hepatocyte and/or human case studies. Urinary markers for the consumption of JWH-210 were the glucuronide of the N-hydroxypentyl metabolite (detectable for 3-4 h) and of RCS-4 the glucuronides of the N-hydroxypentyl, hydroxy-methoxyphenyl (detectable for at least 6 h), and the O-demethyl-hydroxy metabolites (detectable for 4 h). Copyright © 2016 John Wiley & Sons, Ltd.

Time- and temperature-dependent postmortem concentration changes of the (synthetic) cannabinoids JWH-210, RCS-4, as well as ∆9-tetrahydrocannabinol following pulmonary administration to pigs

“…Surgical procedures have already been described elsewhere (Schaefer et al 2015(Schaefer et al , 2016(Schaefer et al , 2017a(Schaefer et al , b, 2018a(Schaefer et al , b, 2019. In brief, ketamine hydrochloride (30 mg/kg, Ursotamin; Serumwerk Bernburg, Bernburg, Germany), xylazine hydrochloride (2.5 mg/kg, Rompun; Bayer, Leverkusen, Germany), and atropine (1 mg, Braun, Melsungen, Germany) were injected for premedication intramusculary.…”

Metabolic Profile of Synthetic Cannabinoids 5F-PB-22, PB-22, XLR-11 and UR-144 by Cunninghamella elegans

“…While providing the most reliable data [15], self-administration of drugs is difficult due to possible side effects and ethical concerns and therefore other approaches are commonly taken such as in vitro human hepatocytes [7][8][9][16][17][18][19][20] and human liver microsomes (HLM) [6,14,[21][22][23][24][25][26], and in vivo animals [5,[25][26][27]. The combination of controlled experiments such as human hepatocytes and authentic human urine analysis particularly appears to be valuable [28,29].…”

Is adipose tissue suitable for detection of (synthetic) cannabinoids? A comparative study analyzing antemortem and postmortem specimens following pulmonary administration of JWH-210, RCS-4, as well as ∆9-tetrahydrocannabinol to pigs

“…Surgical procedures have previously been described (Schaefer et al 2015 , 2016 , 2017a , b , 2018a , b , 2019 , 2020 ). At first, the animals received an intramuscular injection of xylazine hydrochloride (2.5 mg/kg, Rompun; Bayer, Leverkusen, Germany), ketamine hydrochloride (30 mg/kg, Ursotamin; Serumwerk Bernburg, Bernburg, Germany), and atropine (1 mg, Braun, Melsungen, Germany).…”