Please use this identifier to cite or link to this item: doi:10.22028/D291-36852
Title: Going deeper into the toxicokinetics of synthetic cannabinoids: in vitro contribution of human carboxylesterases
Author(s): Wagmann, Lea
Stiller, Rebecca G.
Fischmann, Svenja
Westphal, Folker
Meyer, Markus R.
Language: English
Title: Archives of Toxicology
Publisher/Platform: Springer Nature
Year of Publication: 2022
Free key words: Drugs of abuse
Enzyme kinetics
DDC notations: 610 Medicine and health
Publikation type: Journal Article
Abstract: Synthetic cannabinoids (SC) are new psychoactive substances known to cause intoxications and fatalities. One reason may be the limited data available concerning the toxicokinetics of SC, but toxicity mechanisms are insufficiently understood so far. Human carboxylesterases (hCES) are widely known to play a crucial role in the catalytic hydrolysis of drugs (of abuse). The aim of this study was to investigate the in vitro contribution of hCES to the metabolism of the 13 SC 3,5-AB-5F-FUPPYCA, AB-5F-P7AICA, A-CHMINACA, DMBA-CHMINACA, MBA-CHMINACA, MDMB-4F-BINACA, MDMB-4en-PINACA, MDMB-FUBICA, MDMB-5F-PICA, MMB-CHMICA, MMB-4en-PICA, MMB-FUBINACA, and MPhP-5F-PICA. The SC were incubated with recombinant hCES1b, hCES1c, or hCES2 and analyzed by liquid chromatography–ion trap mass spectrometry to assess amide or ester hydrolysis in an initial activity screening. Enzyme kinetic studies were performed if sufficient hydrolysis was observed. No hydrolysis of the amide linker was observed using those experimental conditions. Except for MDMB-5F-PICA, ester hydrolysis was always detected if an ester group was present in the head group. In general, SC with a terminal ester bearing a small alcohol part and a larger acyl part showed higher affinity to hCES1 isozymes. Due to the low hydrolysis rates, enzyme kinetics could not be modeled for the SC with a tert-leucine-derived moiety, but hydrolysis reactions of MPhP-5F-PICA and of those containing a valine-derived moiety followed classic Michaelis–Menten kinetics. In conclusion, drug–drug/drug–food interactions or hCES polymorphisms may prolong the half-life of SC and the current results help to estimate the risk of toxicity in the future after combining them with activity and clinical data.
DOI of the first publication: 10.1007/s00204-022-03332-z
URL of the first publication:
Link to this record: urn:nbn:de:bsz:291--ds-368528
ISSN: 1432-0738
Date of registration: 18-Jul-2022
Description of the related object: Supplementary Information
Related object:
Faculty: M - Medizinische Fakultät
Department: M - Experimentelle und Klinische Pharmakologie und Toxikologie
Professorship: M - Prof. Dr. Markus Meyer
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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