Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4\xb4-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine

Tanja M Gampfer,Christophe P Stove,Markus R Meyer,Lea Wagmann,Svenja Fischmann,Jennifer Herrmann,Yu Mi Park,Annelies Cannaert,Rolf Müller,Folker Westphal

doi:10.1007/s00204-020-02726-1

Abstract

The two fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine (4F-Cy-BAP) and furanoyl-1-benzyl-4-anilinopiperidine (Fu-BAP) have recently been seized as new psychoactive substances (NPS) on the drugs of abuse market. As their toxicokinetic and toxicodynamic characteristics are completely unknown, this study focused on elucidating their in vitro metabolic stability in pooled human liver S9 fraction (pHLS9), their qualitative in vitro (pHLS9), and in vivo (zebrafish larvae) metabolism, and their in vitro isozyme mapping using recombinant expressed isoenzymes. Their maximum-tolerated concentration (MTC) in zebrafish larvae was studied from 0.01 to 100 µM. Their µ-opioid receptor (MOR) activity was analyzed in engineered human embryonic kidney (HEK) 293 T cells. In total, seven phase I and one phase II metabolites of 4F-Cy-BAP and 15 phase I and four phase II metabolites of Fu-BAP were tentatively identified by means of liquid chromatography high-resolution tandem mass spectrometry, with the majority detected in zebrafish larvae. N-Dealkylation, N-deacylation, hydroxylation, and N-oxidation were the most abundant metabolic reactions and the corresponding metabolites are expected to be promising analytical targets for toxicological analysis. Isozyme mapping revealed the main involvement of CYP3A4 in the phase I metabolism of 4F-Cy-BAP and in terms of Fu-BAP additionally CYP2D6. Therefore, drug-drug interactions by CYP3A4 inhibition may cause elevated drug levels and unwanted adverse effects. MTC experiments revealed malformations and changes in the behavior of larvae after exposure to 100 µM Fu-BAP. Both substances were only able to produce a weak activation of MOR and although toxic effects based on MOR activation seem unlikely, activity at other receptors cannot be excluded.

Highlights

More and more compounds intended to be consumed as substitutes and/or alternatives to classic opioids such as heroin are brought into the drugs of abuse market (Beardsley and1 3 Vol.:(0123456789)Archives of Toxicology (2020) 94:2009–2025Zhang 2018)
Calculations of fu gave values of 0.02 for 4F-Cy-BAP and 0.05 in terms of Fu-BAP resulting in a plasma protein binding (PPB) of 98% (4F-Cy-BAP) and 95% (Fu-BAP). CLh predictions of Fu-BAP in consideration of fu resulted in 0.7 mL/min/kg in both models
The current study focused on the toxicokinetic and toxicodynamic properties of the fentanyl homologs 4F-Cy-BAP and Fu-BAP

Summary

Introduction

They are summarized under the term new synthetic opioids (NSO) and have markedly contributed to the dramatic rise in overdose deaths amongst opioid abusers (Fagiola et al 2018; Guerrieri et al 2017; Muller et al 2019; Sharma et al 2019; Solimini et al 2018). The two fentanyl homologs cyclopropanoyl-1-benzyl4′-fluoro-4-anilinopiperidine (4F-Cy-BAP) and furanoyl1-benzyl-4-anilinopiperidine (Fu-BAP) have been seized in Europe and were intended to be brought onto the market as NSO (EMCDDA 2018). Fu-BAP and related compounds were identified as antagonists at

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