In vitro evaluation of the biotransformation of New Psychoactive Substances (NPS) using the human liver microsome model

Abstract

The New Psychoactive Substances (NPS) are defined as a group of substances (or mixture of substances) with activity in the central nervous system (CNS), produced from molecular modifications in drugs already known as 3,4-methylenedioxymethamphetamine (MDMA) and ketamine. Modifications in the chemical structure of the already large and numerous groups of NPS have been used as a method of evading legislation based on a nominal list of controlled substances. These molecules appear not only as an important legal problem, but also a public health problem, since information about their toxic effects, as well as harm reduction measures related to the use of these substances, are little known and may favor the emergence of severe cases of intoxication. Within this context, synthetic cathinones appear as one of the most expressive groups of NSP, comprising substances that are still poorly studied and in a growing number of reports, such as 3,4-methylenedioxy-PV8 and eutylone. Therefore, the determination of biotransformation mechanisms of these molecules and the identification of their respective metabolites, in addition to the enzymes involved in such processes, is extremely important to determine their toxicities. The development of such information is essential in the evaluation and prediction of the effects of these substances, providing parameters about their activities, interactions, toxicities, possible treatments and laboratory diagnosis of intoxications. In this context, the use of in vitro methods for evaluating the metabolization profile, such as the human liver microsomes model (HLM), presents several advantages due to its simplicity of use, low cost and the presence of all CYP450 isoforms. Thus, this project aims to evaluate the in vitro metabolic profile of two synthetic cathinones that still do not have data about their biotransformation processes in the literature, 3,4-methylenedioxy-PV8 and eutylone. Such information will be generated through the use of the HLM model, in order to identify the main biotransformation products generated, in addition to the elucidation of these mechanisms. The project will also present a study of potential inhibitory and/or inducing actions of these substances on the enzymes responsible for the biotransformation process, which are mainly constituted by the enzymes of the CYP450 family.