Distribution of the (synthetic) cannabinoids JWH-210, RCS-4, as well as ∆9-tetrahydrocannabinol following pulmonary administration to pigs

Schaefer, Nadine; Kröll, Ann-Katrin; Körbel, Christina; Laschke, Matthias W.; Menger, Michael D.; Maurer, Hans H.; Meyer, Markus R.; Schmidt, Péter

doi:10.1007/s00204-019-02493-8

Cited by 17 publications

(50 citation statements)

References 23 publications

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“…The buffers were prepared as described elsewhere (Schaefer et al 2015(Schaefer et al , 2019. The acetate buffer (pH 4) was prepared with 5.7 mL of glacial acetic acid and 16 mL of aqueous potassium hydroxide (1 M).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…As already described in a previous study (Schaefer et al 2019), standard stock solutions (1 mg/mL) were prepared by dissolving 5 mg of each solid compound in 5 mL of ethanol. Concentrations of working standard solutions (0.001 mg/ mL, 0.01 mg/mL, 0.1 mg/mL) were obtained by diluting stock solution or liquid reference standards with ethanol, respectively.…”

Section: Calibrators For Standard Additionmentioning

confidence: 99%

“…As described elsewhere (Schaefer et al 2019), twelve domestic male pigs [Swabian Hall strain; body weight (BW) 40.5-49.8 kg] were used for the study. The animals had free access to tap water and daily standard chow.…”

Section: Animalsmentioning

confidence: 99%

“…However, these studies did not provide comprehensive information on the tissue distribution of SC, as only certain organs and/or blood were analyzed, and the distribution of their metabolites has not been examined. Regarding this issue, a pig model suitable for cannabinoid TK studies after pulmonary administration of 4-ethylnaphthalene-1-yl-(1-pentylindole-3-yl)methanone (JWH-210), 2-(4-methoxyphenyl)-1-(1pentyl-indole-3-yl)methanone (RCS-4), and tetrahydrocannabinol (THC) has been established by the authors providing antemortem data on the distribution of SC and their main metabolites in blood (Schaefer et al 2018a, b) as well as perimortem data on the distribution in the different organs at the time of death (Schaefer et al 2019). Pigs were chosen, because they have already been proven to be useful examining postmortem concentration changes of central nervous acting substances (Brunet et al 2010;Crandall et al 2006;Flanagan et al 2003;Hilberg et al 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Following, the PM distribution as well as the time-and temperature-dependent concentration changes of the cannabinoids and their main metabolites should be examined in the present study and results should be compared with those found in the perimortem specimens (Schaefer et al 2019).…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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In forensic toxicology, interpretation of postmortem (PM) drug concentrations might be complicated due to the lack of data concerning drug stability or PM redistribution (PMR). Regarding synthetic cannabinoids (SC), only sparse data are available, which derived from single case reports without any knowledge of dose and time of consumption. Thus, a controlled pig toxicokinetic study allowing for examination of PMR of SC was performed. Twelve pigs received a pulmonary dose of 200 µg/kg BW each of 4-ethylnaphthalene-1-yl-(1-pentylindole-3-yl)methanone (JWH-210), 2-(4-methoxyphenyl)-1-(1pentyl-indole-3-yl)methanone (RCS-4), and Δ9-tetrahydrocannabinol via an ultrasonic nebulizer. Eight hours after, the pigs were put to death with T61 and specimens of relevant tissues and body fluids were collected. Subsequently, the animals were stored at room temperature (n = 6) or 4 °C (n = 6) and further samples were collected after 24, 48, and 72 h each. Concentrations were determined following enzymatic cleavage and solid-phase extraction by liquid-chromatography tandem mass spectrometry applying the standard addition approach. High concentrations of the parent compounds were observed in lung, liver, kidney and bile fluid/duodenum content as well as brain. HO-RCS-4 was the most prevalent metabolite detected in PM specimens. In general, changes of PM concentrations were found in every tissue and body fluid depending on the PM interval as well as storage temperature.

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Section: Chemicals and Reagentsmentioning

confidence: 99%

Section: Calibrators For Standard Additionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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Comparison of in vitro and in vivo models for the elucidation of metabolic patterns of 7‐azaindole‐derived synthetic cannabinoids exemplified using cumyl‐5F‐P7AICA

Walle

Nordmeier

Doerr

et al. 2020

Drug Testing and Analysis

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Due to the dynamic market involving synthetic cannabinoids (SCs), the determination of analytical targets is challenging in clinical and forensic toxicology. SCs usually undergo extensive metabolism, and therefore their main metabolites must be identified for the detection in biological matrices, particularly in urine. Controlled human studies are usually not possible for ethical reasons; thus, alternative models must be used. The aim of this work was to predict the in vitro and in vivo metabolic patterns of 7-azaindole-derived SCs using 1-(5-fluoropentyl)-N-(2-phenylpropan-2-yl)-1Hpyrollo[2,3-b]pyridin-3-carboxamide (cumyl-5F-P7AICA) as an example. Different in vitro (pooled human liver S9 fraction, pooled human liver microsomes, and pig liver microsomes) and in vivo (rat and pig) systems were compared. Monooxygenase isoenzymes responsible for the most abundant phase I steps, namely oxidative defluorination (OF) followed by carboxylation, monohydroxylation, and ketone formation, were identified. In both in vivo models, OF/carboxylation and Ndealkylation/monohydroxylation/sulfation could be detected. Regarding pHS9 and pig urine, monohydroxylation/sulfation or glucuronidation was also abundant. Furthermore, the parent compound could still be detected in all models. Initial monooxygenase activity screening revealed the involvement of CYP2C19, CYP3A4, and CYP3A5. Therefore, in addition to the parent compound, the OF/carboxylated and monohydroxylated (and sulfated or glucuronidated) metabolites can be recommended as urinary targets. In comparison to literature, the pig model predicts best the human metabolic pattern of cumyl-5F-P7AICA. Furthermore, the pig model should be suitable to mirror the time-dependent excretion pattern of parent compounds and metabolites.

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‘Flying high?’—Jump from a height in a ‘Spice’ high?: A case report on the synthetic cannabinoid 5F‐MDMB‐P7AICA

Walle

Doerr

Schmidt

et al. 2022

Drug Testing and Analysis

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Regarding the high potency of synthetic cannabinoids (SC), many intoxications and fatal cases are reported in literature. Here, we report on a fatality with 5F‐MDMB‐P7AICA contributing to the occurrence of death. A 31‐year‐old man died 10 h after he fell from the rooftop of a house. Police investigations revealed that he had consumed a ‘legal high’ herbal blend some hours earlier. An initial toxicological screening for new psychoactive substances (NPS) was negative. One year after, the analysis of confiscated drug samples revealed the SC 5F‐MDMB‐P7AICA being unknown at the time of the first investigations. Hence, post‐mortem specimens were retrospectively analysed for 5F‐MDMB‐P7AICA and its dimethylbutanoic acid (DBA) metabolite. Lung, liver, kidney and bile fluid (BF) of the decedent were analysed following solid‐phase extraction and standard addition, heart blood (HB) and peripheral blood (PB) by fully validated liquid–liquid extraction and protein precipitation methods. Additionally, hair specimens were analysed to examine a possible chronic consumption of the SC. All specimens were analysed by liquid–chromatography tandem mass spectrometry. 5F‐MDMB‐P7AICA was detected in HB (0.69 ng/ml), PB (1.2 ng/ml) and hair. DBA was found in HB (46 ng/ml) and PB (5.7 ng/ml) and could additionally be identified in liver and kidney (approximately 4–5 ng/g), lung (approximately 12 ng/g) and BF (approximately 60 ng/g). Compared with the parent compound, much higher concentrations of DBA were quantified. This case shows that drugs found at the scene can provide helpful initial information for further toxicological screenings in biological samples, especially when there is evidence of NPS consumption.

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Distribution of the (synthetic) cannabinoids JWH-210, RCS-4, as well as ∆9-tetrahydrocannabinol following pulmonary administration to pigs

Cited by 17 publications

References 23 publications

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

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

Comparison of in vitro and in vivo models for the elucidation of metabolic patterns of 7‐azaindole‐derived synthetic cannabinoids exemplified using cumyl‐5F‐P7AICA

‘Flying high?’—Jump from a height in a ‘Spice’ high?: A case report on the synthetic cannabinoid 5F‐MDMB‐P7AICA

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