Strategies to distinguish new synthetic cannabinoid FUBIMINA (BIM-2201) intake from its isomer THJ-2201: metabolism of FUBIMINA in human hepatocytes.

Xingxing Diao,Mingshe Zhu,Marilyn A Huestis,Karl B Scheidweiler,Shaokun Pang,Ariane Wohlfarth

doi:10.1007/s11419-016-0312-2

Abstract

Since 2013, a new drugs-of-abuse trend attempts to bypass drug legislation by marketing isomers of scheduled synthetic cannabinoids (SCs), e.g., FUBIMINA (BIM-2201) and THJ-2201. It is much more challenging to confirm a specific isomer’s intake and distinguish it from its structural analog because the isomers and their major metabolites usually have identical molecular weights and display the same product ions. Here, we investigated isomers FUBIMINA and THJ-2201 and propose strategies to distinguish their consumption. THJ-2201 was scheduled in the US, Japan, and Europe; however, FUBIMINA is easily available on the Internet. We previously investigated THJ-2201 metabolism in human hepatocytes, but human FUBIMINA metabolism is unknown. We aim to characterize FUBIMINA metabolism in human hepatocytes, recommend optimal metabolites to confirm its consumption, and propose strategies to distinguish between intakes of FUBIMINA and THJ-2201. FUBIMINA (10 μM) was incubated in human hepatocytes for 3 h, and metabolites were characterized with high-resolution mass spectrometry (HR-MS). We identified 35 metabolites generated by oxidative defluorination, further carboxylation, hydroxylation, dihydrodiol formation, glucuronidation, and their combinations. We recommend 5′-OH-BIM-018 (M34), BIM-018 pentanoic acid (M33), and BIM-018 pentanoic acid dihydrodiol (M7) as FUBIMINA specific metabolites. THJ-2201 produced specific metabolite markers 5′-OH-THJ-018 (F26), THJ-018 pentanoic acid (F25), and hydroxylated THJ-2201 (F13). Optimized chromatographic conditions to achieve different retention times and careful selection of specific product ion spectra enabled differentiation of isomeric metabolites, in this case FUBIMINA from THJ-2201. Our HR-MS approach should be applicable for differentiating future isomeric SCs, which is especially important when different isomers have different legal status.

Highlights

Synthetic cannabinoids (SCs) were originally developed as tools to study the endogenous endocannabinoid system [1, 2]
THJ-2201 was scheduled in the US, Japan, and Europe; FUBIMINA is available on the Internet
FUBIMINA (10 lM) was incubated in human hepatocytes for 3 h, and metabolites were characterized with high-resolution mass spectrometry (HR-MS)

Summary

Introduction

Synthetic cannabinoids (SCs) were originally developed as tools to study the endogenous endocannabinoid system [1, 2]. Many SCs are CB1 and CB2 receptors agonists, eliciting greater cannabimimetic effects than D9-tetrahydrocannabinol [3, 4]. SC drug abuse can produce significant human toxicity including agitation, seizures, hypertension, emesis, myocardial infarction, and even death [6,7,8,9]. For these reasons, many SCs were scheduled across the globe, and many more structural analogs emerged. Little is known about metabolism of these new SCs, which makes it challenging to document their intake in clinical

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