Synthesized in early 1990s in pharmaceutical research, designer cannabinoids show high affinity at endocannadinoid receptors; despite their antiemetic and pain-relieving therapeutic properties, most of them are not yet approved for human use, mostly because of toxic side effects. Actually, due to their psychoactive properties, synthetic cannabinoids are marked illicitly worldwide as adulterants of herbal products or smoking mixtures claimed to contain only “natural non-illegal” compounds and are widely abused as recreational drugs. At present, they are included in the section S8 “cannabinoids” of the World Anti-Doping Agency List of Prohibited Substances and Methods and their use is prohibited “in competition” only. As they are extensively cleared by hepatic metabolism via oxidative and conjugating enzymes, a thorough knowledge of their main biotransformation pathways is of the utmost importance in order to identify the most appropriate marker(s) to detect their abuse. Here the metabolic profile of synthetic cannabinoids from different chemical classes was characterized. Given the difficulty in finding human urine samples from subjects who admit synthetic cannabinoids assumption and in obtaining permission to perform excretion studies, in vitro approaches based on the use of human liver microsomes and/or of expressed cytochrome P450s (CYPs) and uridine diphosphateglucuronosyltransferases (UGTs) isoforms were used. Our results show that hydroxylation in different position is the most important biotransformation pathway, while the other metabolic reactions observed (i.e. dealkylation, carboxylation, etc) are strictly linked to the chemical class under investigation and to the substituents present in each basic structure. Furthermore, our data also show that the isoenzymes mainly involved in the phase I reaction are the CYP1A2, CYP2C19, CYP2D6 and the CYP3A subfamily, whereas those involved in phase II metabolism are the UGT2B7, UGT1A3 and UGT1A10.
Characterization of the main biotransformation pathways of synthetic cannabinoids from different chemical classes / I., Fiacco; Botre', Francesco; M., Capodaglio; X., de la Torre; M., Mazzarino. - ELETTRONICO. - 22:(2014), pp. 22-29. (Intervento presentato al convegno MANFRED DONIKE WORKSHOP ON DOPE ANALYSIS tenutosi a COLONIA nel 2014).
Characterization of the main biotransformation pathways of synthetic cannabinoids from different chemical classes
BOTRE', Francesco;
2014
Abstract
Synthesized in early 1990s in pharmaceutical research, designer cannabinoids show high affinity at endocannadinoid receptors; despite their antiemetic and pain-relieving therapeutic properties, most of them are not yet approved for human use, mostly because of toxic side effects. Actually, due to their psychoactive properties, synthetic cannabinoids are marked illicitly worldwide as adulterants of herbal products or smoking mixtures claimed to contain only “natural non-illegal” compounds and are widely abused as recreational drugs. At present, they are included in the section S8 “cannabinoids” of the World Anti-Doping Agency List of Prohibited Substances and Methods and their use is prohibited “in competition” only. As they are extensively cleared by hepatic metabolism via oxidative and conjugating enzymes, a thorough knowledge of their main biotransformation pathways is of the utmost importance in order to identify the most appropriate marker(s) to detect their abuse. Here the metabolic profile of synthetic cannabinoids from different chemical classes was characterized. Given the difficulty in finding human urine samples from subjects who admit synthetic cannabinoids assumption and in obtaining permission to perform excretion studies, in vitro approaches based on the use of human liver microsomes and/or of expressed cytochrome P450s (CYPs) and uridine diphosphateglucuronosyltransferases (UGTs) isoforms were used. Our results show that hydroxylation in different position is the most important biotransformation pathway, while the other metabolic reactions observed (i.e. dealkylation, carboxylation, etc) are strictly linked to the chemical class under investigation and to the substituents present in each basic structure. Furthermore, our data also show that the isoenzymes mainly involved in the phase I reaction are the CYP1A2, CYP2C19, CYP2D6 and the CYP3A subfamily, whereas those involved in phase II metabolism are the UGT2B7, UGT1A3 and UGT1A10.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
