<i>In vitro</i> and <i>in vivo</i> human metabolism of the synthetic cannabinoid AB‐CHMINACA

Drug Testing and Analysis - Tập 7 Số 10 - Trang 866-876 - 2015
Claudio Erratico1, Noelia Negreira1, Helia Norouzizadeh1, Adrian Covaci1, Hugo Neels1, Kristof E. Maudens1, Alexander L.N. van Nuijs1
1Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium

Tóm tắt

N‐[(1S)‐1‐(aminocarbonyl)‐2‐methylpropyl]‐1‐(cyclohexylmethyl)‐1H‐indazole‐3‐carboxamide (AB‐CHMINACA) is a recently introduced synthetic cannabinoid. At present, no information is available about in vitro or in vivo human metabolism of AB‐CHMINACA. Therefore, biomonitoring studies to screen AB‐CHMINACA consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated the in vitro metabolism of AB‐CHMINACA using human liver microsomes (HLMs). Formation of AB‐CHMINACA metabolites was monitored using liquid chromatography coupled to time‐of‐flight mass spectrometry. Twenty‐six metabolites of AB‐CHMINACA were detected including seven mono‐hydroxylated and six di‐hydroxylated metabolites and a metabolite resulting from N‐dealkylation of AB‐CHMINACA, all produced by cytochrome P450 (CYP) enzymes. Two carboxylated metabolites, likely produced by amidase enzymes, and five glucuronidated metabolites were also formed. Five mono‐hydroxylated and one carboxylated metabolite were likely the major metabolites detected. The involvement of individual CYPs in the formation of AB‐CHMINACA metabolites was tested using a panel of seven human recombinant CYPs (rCYPs). All the hydroxylated AB‐CHMINACA metabolites produced by HLMs were also produced by the rCYPs tested, among which rCYP3A4 was the most active enzyme. Most of the in vitro metabolites of AB‐CHMINACA were also present in urine obtained from an AB‐CHMINACA user, therefore showing the reliability of the results obtained using the in vitro metabolism experiments conducted to predict AB‐CHMINACA in vivo metabolism. The AB‐CHMINACA metabolites to target in biomonitoring studies using urine samples are now reliably identified and can be used for routine analysis. Copyright © 2015 John Wiley & Sons, Ltd.

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Tài liệu tham khảo

United Nations Office on Drugs and Crime.The Challenge of New Psychoactive Substances A Report from the Global SMART Programme. United Nations Office of Drugs and Crime Vienna Austria 2013.

European Monitoring Center for Drugs and Drug Addiction (EMCDDA).Perspectives on drugs: Synthetic cannabinoids in Europe. Available athttp://www.emcdda.europa.eu/attachements.cfm/att_212361_EN_EMCDDA_POD_2013_Synthetic%20cannabinoids.pdf[3 February 2015].

10.1111/j.1476-5381.2009.00582.x

10.1371/journal.pone.0021917

Ward S. J., 1990, Aminoalkylindoles (AAIs): A new route to the cannabinoid receptor?, NIDA Res. Monogr., 105, 425

10.2174/1389557054368772

10.1111/j.1365-2044.2001.02269.x

10.1007/s40429-014-0014-y

10.1002/dta.1584

10.1007/s11419-014-0238-5

10.1007/s11419-012-0171-4

10.1007/s11419-014-0245-6

Drug Enforcement Administration, U.S. Department of Justice, 2014, Schedules of Controlled Substances: Temporary Placement of Three Synthetic Cannabinoids Into Schedule I, Fed. Regist., 79, 75767

10.1002/dta.1731

10.1002/bmc.3155

10.1002/jps.1031

Subrahmanyam V., 2001, Identification of cytochrome P‐450 isoforms responsible for cis‐tradamdol metabolism in human liver microsomes, Drug Metab. Dispos., 29, 1146

10.1146/annurev.pharmtox.40.1.581

10.1124/dmd.112.045096

10.1016/S0960-0760(99)00088-6

Hasegawa J., 1982, Apparent intramolecular acyl migration of zomepirac glucuronide, Drug Metab. Dispos., 10, 469

10.1002/chir.10047

10.1111/j.1556-4029.2012.02261.x

10.1208/s12248-013-9516-0

10.1007/s00216-014-7668-0

10.1002/dta.1418

10.1007/s00216-010-4171-0

10.1373/clinchem.2013.209965

10.1124/dmd.112.047530

Shimada T., 1994, Interindividual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens, and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians, J. Pharmacol. Exp. Ther., 270, 414

10.1124/dmd.105.008672

Wrighton S. A., 1990, Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3), Mol. Pharmacol., 38, 207

10.1007/0-387-27447-2_10

10.1006/abbi.1997.0302

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