Distribution of Synthetic Cannabinoids JWH-210, RCS-4 and Δ 9-Tetrahydrocannabinol After Intravenous Administration to Pigs

Overview

Journal Curr Neuropharmacol

Publisher Bentham Science Publishers

Date 2016 Nov 12

PMID 27834143

Citations 11

Authors

Nadine Schaefer

Mattias Kettner

Matthias W Laschke

Julia Schlote

Andreas H Ewald

Michael D Menger

Hans H Maurer

Peter H Schmidt

Affiliations

Soon will be listed here.

Abstract

Background: Synthetic cannabinoids (SCs) have become an increasing issue in forensic toxicology. Controlled human studies evaluating pharmacokinetic data of SCs are lacking and only few animal studies have been published. Thus, an interpretation of analytical results found in intoxicated or poisoned individuals is difficult. Therefore, the distribution of two selected 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) as well as Δ9-tetrahydrocannabinol (THC) as reference were examined in pigs.

Methods: Pigs (n = 6 per drug) received a single intravenous 200 μg/kg BW dose of JWH-210, RCS- 4, or THC. Six hours after administration, the animals were exsanguinated and relevant organs, important body fluids such as bile, and tissues such as muscle and adipose tissue, as well as the bradytrophic specimens dura and vitreous humor were collected. After hydrolysis and solid phase extraction, analysis was performed by LC-MS/MS. To overcome matrix effects of the LC-MS/MS analysis, a standard addition method was applied for quantification.

Results: The parent compounds could be detected in every analyzed specimen with the exception of THC that was not present in dura and vitreous humor. Moderate concentrations were present in brain, the site of biological effect. Metabolite concentrations were highest in tissues involved in metabolism and/or elimination Conclusions: Besides kidneys and lungs routinely analyzed in postmortem toxicology, brain, adipose, and muscle tissue could serve as alternative sources, particularly if other specimens are not available. Bile fluid is the most appropriate specimen for SCs and THC metabolites detection.

Citing Articles

Does a carboxamide moiety alter the toxicokinetics of synthetic cannabinoids? A study after pulmonary and intravenous administration of cumyl-5F-P7AICA to pigs.

Walle N, Dings C, Zaher O, Doerr A, Peters B, Laschke M Arch Toxicol. 2024; 99(2):633-643.

PMID: 39630204 PMC: 11775056. DOI: 10.1007/s00204-024-03906-z.

Endocannabinoid system and phytocannabinoids in the main species of veterinary interest: a comparative review.

Di Salvo A, Chiaradia E, Sforna M, Rocca G Vet Res Commun. 2024; 48(5):2915-2941.

PMID: 39162768 PMC: 11442603. DOI: 10.1007/s11259-024-10509-7.

Does a postmortem redistribution affect the concentrations of the 7 azaindole-derived synthetic cannabinoid 5F-MDMB-P7AICA in tissues and body fluids following pulmonary administration to pigs?.

Doerr A, Nordmeier F, Walle N, Laschke M, Menger M, Meyer M Arch Toxicol. 2024; 98(10):3289-3298.

PMID: 38955864 PMC: 11402846. DOI: 10.1007/s00204-024-03815-1.

Unexpected results found in larvae samples from two postmortem forensic cases.

Groth O, Franz S, Fels H, Krueger J, Roider G, Dame T Forensic Toxicol. 2022; 40(1):144-155.

PMID: 36454495 PMC: 9715440. DOI: 10.1007/s11419-021-00601-x.

An Update on the Implications of New Psychoactive Substances in Public Health.

Simao A, Antunes M, Cabral E, Oliveira P, Rosendo L, Brinca A Int J Environ Res Public Health. 2022; 19(8).

PMID: 35457736 PMC: 9028227. DOI: 10.3390/ijerph19084869.

References

Behonick G, Shanks K, Firchau D, Mathur G, Lynch C, Nashelsky M . Four postmortem case reports with quantitative detection of the synthetic cannabinoid, 5F-PB-22. J Anal Toxicol. 2014; 38(8):559-62. PMC: 4334789. DOI: 10.1093/jat/bku048. View

Ryan U, Grantham C . Metabolism of endogenous and xenobiotic substances by pulmonary vascular endothelial cells. Pharmacol Ther. 1989; 42(2):235-50. DOI: 10.1016/0163-7258(89)90037-5. View

Schaefer N, Peters B, Bregel D, Maurer H, Schmidt P, Ewald A . Can JWH-210 and JWH-122 be detected in adipose tissue four weeks after single oral drug administration to rats?. Biomed Chromatogr. 2014; 28(8):1043-7. DOI: 10.1002/bmc.3137. View

Hermanns-Clausen M, Kithinji J, Spehl M, Angerer V, Franz F, Eyer F . Adverse effects after the use of JWH-210 - a case series from the EU Spice II plus project. Drug Test Anal. 2016; 8(10):1030-1038. DOI: 10.1002/dta.1936. View

Huffman J, Zengin G, Wu M, Lu J, Hynd G, Bushell K . Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists. Bioorg Med Chem. 2004; 13(1):89-112. DOI: 10.1016/j.bmc.2004.09.050. View

Castaneto M, Gorelick D, Desrosiers N, Hartman R, Pirard S, Huestis M . Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications. Drug Alcohol Depend. 2014; 144:12-41. PMC: 4253059. DOI: 10.1016/j.drugalcdep.2014.08.005. View

Bode G, Clausing P, Gervais F, Loegsted J, Luft J, Nogues V . The utility of the minipig as an animal model in regulatory toxicology. J Pharmacol Toxicol Methods. 2010; 62(3):196-220. DOI: 10.1016/j.vascn.2010.05.009. View

Gandhi A, Zhu M, Pang S, Wohlfarth A, Scheidweiler K, Huestis M . Metabolite profiling of RCS-4, a novel synthetic cannabinoid designer drug, using human hepatocyte metabolism and TOF-MS. Bioanalysis. 2014; 6(11):1471-85. PMC: 4159359. DOI: 10.4155/bio.14.13. View

Trecki J, Gerona R, Schwartz M . Synthetic Cannabinoid-Related Illnesses and Deaths. N Engl J Med. 2015; 373(2):103-7. DOI: 10.1056/NEJMp1505328. View

10.

Brents L, Reichard E, Zimmerman S, Moran J, Fantegrossi W, Prather P . Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS One. 2011; 6(7):e21917. PMC: 3130777. DOI: 10.1371/journal.pone.0021917. View

11.

Shanks K, Dahn T, Terrell A . Detection of JWH-018 and JWH-073 by UPLC-MS-MS in postmortem whole blood casework. J Anal Toxicol. 2012; 36(3):145-52. DOI: 10.1093/jat/bks013. View

12.

Bend J, Philpot R . The pulmonary uptake, accumulation, and metabolism of xenobiotics. Annu Rev Pharmacol Toxicol. 1985; 25:97-125. DOI: 10.1146/annurev.pa.25.040185.000525. View

13.

Levisky J, BOWERMAN D, Jenkins W, Johnson D, Karch S . Drugs in postmortem adipose tissues: evidence of antemortem deposition. Forensic Sci Int. 2001; 121(3):157-60. DOI: 10.1016/s0379-0738(01)00397-8. View

14.

Johansson E, Noren K, Sjovall J, Halldin M . Determination of delta 1-tetrahydrocannabinol in human fat biopsies from marihuana users by gas chromatography-mass spectrometry. Biomed Chromatogr. 1989; 3(1):35-8. DOI: 10.1002/bmc.1130030109. View

15.

Banister S, Moir M, Stuart J, Kevin R, Wood K, Longworth M . Pharmacology of Indole and Indazole Synthetic Cannabinoid Designer Drugs AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, and 5F-ADBICA. ACS Chem Neurosci. 2015; 6(9):1546-59. DOI: 10.1021/acschemneuro.5b00112. View

16.

Gronewold A, Skopp G . A preliminary investigation on the distribution of cannabinoids in man. Forensic Sci Int. 2011; 210(1-3):e7-e11. DOI: 10.1016/j.forsciint.2011.04.010. View

17.

Labay L, Caruso J, Gilson T, Phipps R, Knight L, Lemos N . Synthetic cannabinoid drug use as a cause or contributory cause of death. Forensic Sci Int. 2016; 260:31-39. DOI: 10.1016/j.forsciint.2015.12.046. View

18.

Cha H, Seong Y, Song M, Jeong H, Shin J, Yun J . Neurotoxicity of Synthetic Cannabinoids JWH-081 and JWH-210. Biomol Ther (Seoul). 2015; 23(6):597-603. PMC: 4624077. DOI: 10.4062/biomolther.2015.057. View

19.

Schaefer N, Kettner M, Laschke M, Schlote J, Peters B, Bregel D . Simultaneous LC-MS/MS determination of JWH-210, RCS-4, ∆(9)-tetrahydrocannabinol, and their main metabolites in pig and human serum, whole blood, and urine for comparing pharmacokinetic data. Anal Bioanal Chem. 2015; 407(13):3775-86. DOI: 10.1007/s00216-015-8605-6. View

20.

Chimalakonda K, Seely K, Bratton S, Brents L, Moran C, Endres G . Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos. 2012; 40(11):2174-84. PMC: 3477201. DOI: 10.1124/dmd.112.047530. View