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In vitro and in vivo metabolisms of 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122)

Nik De Brabanter (UGent) , Simone Esposito (UGent) , Lore Geldof (UGent) , Leen Lootens (UGent) , Philip Meuleman (UGent) , Geert Leroux-Roels (UGent) , Koen Deventer (UGent) and Peter Van Eenoo (UGent)
(2013) FORENSIC TOXICOLOGY. 31(2). p.212-222
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Abstract
1-Pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122) is an agonist of the cannabinoid receptors CB 1 and CB 2. In this study, the phase I and phase II metabolisms of JWH-122 were investigated using two models. In vitro studies using incubations of JWH-122 with human liver microsomes were performed to obtain metabolites of the drug at the initial step; 11 classes of metabolites were found and analyzed by liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS-MS). Hydroxylation(s) on the naphthalene moiety and/or the indole moiety of the molecule took place as such or in combination with dehydrogenation or cleavage of the N-pentyl side chain. Furthermore also dihydrodiol metabolites are formed probably via epoxide formation on the naphthalene moiety, irrespective of the combination with hydroxylation(s). A metabolite carrying a carboxylgroup on the N-pentyl side chain was also detected. As the second step of the study, in vivo experiments, using chimeric mice were performed; the mice were orally administered JWH-122, and their urine samples were collected to be subjected to enzymatic hydrolysis, followed by the LC-MS and LC-MS-MS analyses. The urine samples without hydrolysis were also analyzed for their molecular formulae in the conjugated forms by LC-high resolution MS. The in vivo model using chimeric mice could confirm most metabolite classes and clarify the phase II metabolism of JWH-122. From these results, it can be concluded that all metabolites formed in vivo are excreted conjugated as glucuronide or sulfate, with conjugation rates above 50%.
Keywords
phase II metabolism, LC-MS(-MS), In vivo models, Synthetic cannabinoids, JWH-122 metabolites, Chimeric mice, Phase I metabolism, In vitro models, SYNTHETIC CANNABINOIDS, HUMANIZED LIVER, DRUG-METABOLISM, CHIMERIC MICE, HUMAN URINE, IDENTIFICATION, QUANTITATION, JWH-018, AGONIST, ABUSE

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Chicago
De Brabanter, Nik, Simone Esposito, Lore Geldof, Leen Lootens, Philip Meuleman, Geert Leroux-Roels, Koen Deventer, and Peter Van Eenoo. 2013. “In Vitro and in Vivo Metabolisms of 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122).” Forensic Toxicology 31 (2): 212–222.
APA
De Brabanter, N., Esposito, S., Geldof, L., Lootens, L., Meuleman, P., Leroux-Roels, G., Deventer, K., et al. (2013). In vitro and in vivo metabolisms of 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122). FORENSIC TOXICOLOGY, 31(2), 212–222.
Vancouver
1.
De Brabanter N, Esposito S, Geldof L, Lootens L, Meuleman P, Leroux-Roels G, et al. In vitro and in vivo metabolisms of 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122). FORENSIC TOXICOLOGY. 2013;31(2):212–22.
MLA
De Brabanter, Nik, Simone Esposito, Lore Geldof, et al. “In Vitro and in Vivo Metabolisms of 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122).” FORENSIC TOXICOLOGY 31.2 (2013): 212–222. Print.
@article{3095855,
  abstract     = {1-Pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122) is an agonist of the cannabinoid receptors CB 1 and CB 2. In this study, the phase I and phase II metabolisms of JWH-122 were investigated using two models. In vitro studies using incubations of JWH-122 with human liver microsomes were performed to obtain metabolites of the drug at the initial step; 11 classes of metabolites were found and analyzed by liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS-MS). Hydroxylation(s) on the naphthalene moiety and/or the indole moiety of the molecule took place as such or in combination with dehydrogenation or cleavage of the N-pentyl side chain. Furthermore also dihydrodiol metabolites are formed probably via epoxide formation on the naphthalene moiety, irrespective of the combination with hydroxylation(s). A metabolite carrying a carboxylgroup on the N-pentyl side chain was also detected. As the second step of the study, in vivo experiments, using chimeric mice were performed; the mice were orally administered JWH-122, and their urine samples were collected to be subjected to enzymatic hydrolysis, followed by the LC-MS and LC-MS-MS analyses. The urine samples without hydrolysis were also analyzed for their molecular formulae in the conjugated forms by LC-high resolution MS. The in vivo model using chimeric mice could confirm most metabolite classes and clarify the phase II metabolism of JWH-122. From these results, it can be concluded that all metabolites formed in vivo are excreted conjugated as glucuronide or sulfate, with conjugation rates above 50\%.},
  author       = {De Brabanter, Nik and Esposito, Simone and Geldof, Lore and Lootens, Leen and Meuleman, Philip and Leroux-Roels, Geert and Deventer, Koen and Van Eenoo, Peter},
  issn         = {1860-8965},
  journal      = {FORENSIC TOXICOLOGY},
  keyword      = {phase II metabolism,LC-MS(-MS),In vivo models,Synthetic cannabinoids,JWH-122 metabolites,Chimeric mice,Phase I metabolism,In vitro models,SYNTHETIC CANNABINOIDS,HUMANIZED LIVER,DRUG-METABOLISM,CHIMERIC MICE,HUMAN URINE,IDENTIFICATION,QUANTITATION,JWH-018,AGONIST,ABUSE},
  language     = {eng},
  number       = {2},
  pages        = {212--222},
  title        = {In vitro and in vivo metabolisms of 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122)},
  url          = {http://dx.doi.org/10.1007/s11419-013-0179-4},
  volume       = {31},
  year         = {2013},
}

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