Diagnosing intake and rationalizing toxicities associated with 5F-MDMB-PINACA and 4F-MDMB-BINACA abuse
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TOXICOKINETICS AND METABOLISM
Diagnosing intake and rationalizing toxicities associated with 5F‑MDMB‑PINACA and 4F‑MDMB‑BINACA abuse Wen Lie1 · Eleanor Jing Yi Cheong1 · Evelyn Mei Ling Goh2 · Hooi Yan Moy2 · Annelies Cannaert3 · Christophe P. Stove3 · Eric Chun Yong Chan1 Received: 5 September 2020 / Accepted: 5 November 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 OAT3mediated 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 4F-MDMB-BINACA · 5F-MDMB-PINACA · Ester hydrolysis metabolites · Metabolic reaction phenotyping · Transporter-mediated disposition kinetics · In vitro CB1 and CB2 activation analyses
Wen Lie and Eleanor Jing Yi Cheong have contributed equally as co-first authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02948-3) contains supplementary material, which is available to authorized users. * Eric Chun Yong Chan [email protected] 1
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore
2
Analytical Toxicology Laboratory, Applied Sciences Group, Health Sciences Authority, 11 Outram Road, Singapore 169078,
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