Universität zu Köln

Gaunitz, Franziska, Dahm, Patrick, Mogler, Lukas, Thomas, Andreas ORCID: 0000-0003-1199-0743, Thevis, Mario and Mercer-Chalmers-Bender, Katja ORCID: 0000-0002-3843-9065 (2019). In vitro metabolic profiling of synthetic cannabinoids by pooled human liver microsomes, cytochrome P450 isoenzymes, and Cunninghamella elegans and their detection in urine samples. Anal. Bioanal. Chem., 411 (16). S. 3561 - 3580. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1618-2650

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Abstract

As synthetic cannabinoids are extensively metabolized, there is an urgent need for data on which metabolites can be used for successful urine screening. This study examines the in vitro metabolism of EG-018 and its 5F-analogue EG-2201 by means of comparing three different in vitro models: pooled human liver microsomes, cytochrome P450 isoenzymes, and a fungal approach utilizing the filamentous fungus Cunninghamella elegans LENDNER, which is known for its ability to mimic human biotransformation of xenobiotics. In addition, this study includes the screening of two authentic urine samples from individuals with proven EG-018 consumption, for the evaluation of in vitro-in vivo extrapolations made in the study. Incubation with pooled human liver microsomes yielded 15 metabolites of EG-018 belonging to six different metabolite subgroups, and 21 metabolites of EG-2201 belonging to seven different metabolite subgroups, respectively. Incubation with cytochrome P450 isoenzymes incubation yielded a further three EG-018 and five EG-2201 metabolites. With reference to their summed metabolite peak abundancies, the isoenzymes CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were shown to contribute most to the microsomal metabolism of EG-018 and EG-2201. CYP2B6 was shown to make the lowest contribution, by far. As the phase I metabolism of both synthetic cannabinoids was shown to be distributed over a substantial number of different cytochrome P450 isoenzymes, it was concluded that it is likely to not be significantly affected by co-consumption of other drugs. Although fungal incubation with Cunninghamella elegans yielded an additional three EG-018 and four EG-2201 metabolites not observed after microsomal incubation, metabolites generated by Cunninghamella elegans were in good correlation with those generated by microsomal incubations. The fungal model demonstrated its ability to be an independent in vitro model in synthetic cannabinoid metabolism research. The three tested in vitro models enable sufficient predictive in vitro-in vivo extrapolations, comparable to those obtained from hepatocyte incubation published in the literature. In addition, with regard to the screening of authentic urine samples and comparison with the literature, one monohydroxylated EG-018 metabolite and two monohydroxylated EG-2201 metabolites can be recommended as urinary targets, on the basis of the tested in vitro models.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gaunitz, Franziska UNSPECIFIED UNSPECIFIED UNSPECIFIED Dahm, Patrick UNSPECIFIED UNSPECIFIED UNSPECIFIED Mogler, Lukas UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomas, Andreas UNSPECIFIED orcid.org/0000-0003-1199-0743 UNSPECIFIED Thevis, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED Mercer-Chalmers-Bender, Katja UNSPECIFIED orcid.org/0000-0002-3843-9065 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-146396
DOI:	10.1007/s00216-019-01837-8
Journal or Publication Title:	Anal. Bioanal. Chem.
Volume:	411
Number:	16
Page Range:	S. 3561 - 3580
Date:	2019
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1618-2650
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language OXIDATIVE-METABOLISM; HUMAN HEPATOCYTES; ORGANIC-SOLVENTS; DRUG-METABOLISM; IDENTIFICATION; JWH-018; BIOTRANSFORMATION; ELUCIDATION; AM-2201; UR-144 Multiple languages Biochemical Research Methods; Chemistry, Analytical Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14639