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Synthetic cannabimimetic agents metabolized by carboxylesterases.

Publication ,  Journal Article
Thomsen, R; Nielsen, LM; Holm, NB; Rasmussen, HB; Linnet, K; INDICES Consortium,
Published in: Drug Test Anal
July 2015

Synthetic cannabimimetic agents are a large group of diverse compounds which act as agonists at cannabinoid receptors. Since 2004, synthetic cannabinoids have been used recreationally, although several of the compounds have been shown to cause severe toxicity in humans. In this study, the metabolism of two indazole carboxamide derivatives, AB-PINACA and AB-FUBINACA, was investigated by using human liver microsomes (HLM). For both compounds, a major metabolic pathway was the enzymatic hydrolysis of the primary amide, resulting in the major metabolites AB-PINACA-COOH and AB-FUBINACA-COOH. Other major metabolic pathways were mono-hydroxylation of the N-pentyl chain in AB-PINACA and mono-hydroxylation of the 1-amino-3-methyl-1-oxobutane moiety in AB-FUBINACA. To identify the enzyme(s) responsible for the amide hydrolysis, incubations with recombinant carboxylesterases and human serum, as well as inhibition studies in HLM and human pulmonary microsomes (HPM) were performed. Carboxylesterase 1 (CES1) was identified as the major human hepatic and pulmonary enzyme responsible for the amide hydrolysis.We employed similar studies to identify the esterase(s) involved in the previously described hydrolytic metabolism of two quinolineindole synthetic cannabinoids, PB-22 and 5F-PB-22, as well as the closely related compound, BB-22. Our investigations again revealed CES1 to be the key enzyme catalyzing these reactions. The identified major metabolites of AB-PINACA and AB-FUBINACA are likely to be useful in documenting drug usage in forensic and clinical screening. Additionally, the identification of CES1 as the main enzyme hydrolyzing these compounds improves our knowledge in the emerging field of xenobiotic metabolism by esterases.

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Published In

Drug Test Anal

DOI

EISSN

1942-7611

Publication Date

July 2015

Volume

7

Issue

7

Start / End Page

565 / 576

Location

England

Related Subject Headings

  • Microsomes, Liver
  • Male
  • Humans
  • Female
  • Carboxylic Ester Hydrolases
  • Cannabinoids
  • Biomimetic Materials
  • Analytical Chemistry
  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences
 

Citation

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Thomsen, R., Nielsen, L. M., Holm, N. B., Rasmussen, H. B., Linnet, K., & INDICES Consortium, . (2015). Synthetic cannabimimetic agents metabolized by carboxylesterases. Drug Test Anal, 7(7), 565–576. https://doi.org/10.1002/dta.1731
Thomsen, Ragnar, Line M. Nielsen, Niels B. Holm, Henrik B. Rasmussen, Kristian Linnet, and Kristian INDICES Consortium. “Synthetic cannabimimetic agents metabolized by carboxylesterases.Drug Test Anal 7, no. 7 (July 2015): 565–76. https://doi.org/10.1002/dta.1731.
Thomsen R, Nielsen LM, Holm NB, Rasmussen HB, Linnet K, INDICES Consortium. Synthetic cannabimimetic agents metabolized by carboxylesterases. Drug Test Anal. 2015 Jul;7(7):565–76.
Thomsen, Ragnar, et al. “Synthetic cannabimimetic agents metabolized by carboxylesterases.Drug Test Anal, vol. 7, no. 7, July 2015, pp. 565–76. Pubmed, doi:10.1002/dta.1731.
Thomsen R, Nielsen LM, Holm NB, Rasmussen HB, Linnet K, INDICES Consortium. Synthetic cannabimimetic agents metabolized by carboxylesterases. Drug Test Anal. 2015 Jul;7(7):565–576.
Journal cover image

Published In

Drug Test Anal

DOI

EISSN

1942-7611

Publication Date

July 2015

Volume

7

Issue

7

Start / End Page

565 / 576

Location

England

Related Subject Headings

  • Microsomes, Liver
  • Male
  • Humans
  • Female
  • Carboxylic Ester Hydrolases
  • Cannabinoids
  • Biomimetic Materials
  • Analytical Chemistry
  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences