Diagnosing intake and rationalizing toxicities associated with 5F-MDMB-PINACA and 4F-MDMB-BINACA abuse
- 24 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Archives of Toxicology
- Vol. 95 (2), 489-508
- https://doi.org/10.1007/s00204-020-02948-3
Abstract
5F-MDMB-PINACA and 4F-MDMB-BINACA are synthetic cannabinoids (SCs) that elicit cannabinoid psychoactive effects. Defining pharmacokinetic–pharmacodynamic (PK–PD) relationships governing SCs and their metabolites are paramount to investigating their in vivo toxicological outcomes. However, the disposition kinetics and cannabinoid receptor (CB) activities of the primary metabolites of SCs are largely unknown. Additionally, reasons underlying the selection of ester hydrolysis metabolites (EHMs) as urinary biomarkers are often unclear. Here, metabolic reaction phenotyping was performed to identify key metabolizing enzymes of the parent SCs. Hepatic clearances of parent SCs and their EHMs were estimated from microsomal metabolic stability studies. Renal clearances were simulated using a mechanistic kidney model incorporating in vitro permeability and organic anionic transporter 3 (OAT3)-mediated uptake data. Overall clearances were considered in tandem with estimated volumes of distribution for in vivo biological half-lives (t1/2) predictions. Interactions of the compounds with CB1 and CB2 were investigated using a G-protein coupled receptor activation assay. We demonstrated that similar enzymatic isoforms were implicated in the metabolism of 5F-MDMB-PINACA and 4F-MDMB-BINACA. Our in vivo t1/2 determinations verified the rapid elimination of parent SCs and suggest prolonged circulation of their EHMs. The pronounced attenuation of the potencies and efficacies of the metabolites against CB1 and CB2 further suggests how toxic manifestations of SC abuse are likely precipitated by augmented exposure to parent SCs. Notably, basolateral OAT3-mediated uptake of the EHMs substantiates their higher urinary abundance. These novel insights underscore the importance of mechanistic, quantitative and systematic characterization of PK–PD relationships in rationalizing the toxicities of SCs.Keywords
Funding Information
- Research Foundation-Flanders (FWO; 12Y9520N)
- Ghent University - Special Research Fund (01N00814, 01J15517)
This publication has 38 references indexed in Scilit:
- Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug SamplesFrontiers in Chemistry, 2019
- New Synthetic Cannabinoids Metabolism and Strategies to Best Identify Optimal Marker MetabolitesFrontiers in Chemistry, 2019
- Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid ReceptorsJournal of Pharmacology and Experimental Therapeutics, 2018
- Cannabinoid-like effects of five novel carboxamide synthetic cannabinoidsNeuroToxicology, 2018
- Activity-Based Detection of Consumption of Synthetic Cannabinoids in Authentic Urine Samples Using a Stable Cannabinoid Reporter SystemAnalytical Chemistry, 2017
- Approaches, Challenges, and Advances in Metabolism of New Synthetic Cannabinoids and Identification of Optimal Urinary Marker MetabolitesClinical Pharmacology & Therapeutics, 2016
- Detection and Activity Profiling of Synthetic Cannabinoids and Their Metabolites with a Newly Developed BioassayAnalytical Chemistry, 2016
- Synthetic cannabinoids pharmacokinetics and detection methods in biological matricesDrug Metabolism Reviews, 2015
- Synthetic Cannabinoid Intoxication: A Case Series and ReviewThe Journal of Emergency Medicine, 2013
- Utility of Intersystem Extrapolation Factors in Early Reaction Phenotyping and the Quantitative Extrapolation of Human Liver Microsomal Intrinsic Clearance Using Recombinant Cytochromes P450Drug Metabolism and Disposition, 2010