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SOFT 2014 Meeting Abstracts.Pdf Abstracts Of Platform Presentations S-01 Urinary Markers for AB-FUBINACA Intake Determined by Human Hepatocytes Incubation and High- Resolution Mass Spectrometry Marisol S. Castaneto*1,2, Ariane Wohlfarth1, Shaokun Pang3, Mingshe Zhu4, Karl B. Scheidweiler1 and Marilyn A. Huestis1; 1Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA; 2Program in Toxicology, University of Maryland Baltimore, Baltimore, MD, USA; 3Department of Biotransformation, Bristol-Myers Squibb Research and Development, Princeton, NJ, USA; 4AB SCIEX, Foster City, CA, USA Introduction: Synthetic cannabinoids (SC) intake increased worldwide, with purported psychotropic effects documented in drug user blogs, poison control call centers, driving under the influence of drugs, and emergency room visits. Although multiple SC classes are now DEA controlled, new cannabimimetic compounds continue to emerge. It is critically important to identify urinary SC targets to document SC intake, to link adverse effects with specific SC, and to educate the public on the dangers of designer drug use. Recently, our laboratory conducted metabolite-profiling studies of SC with human hepatocytes incubation, high resolution mass spectrometry (HRMS), and data-mining software. AB-FUBINACA, N-(1-amino-3-methyl-1-oxabutan-2-yl)-1-(4- fluorobenzyl)-1H-indazole-3-carboxamide, is a scheduled indazole derivative SC originally identified in Japanese seized herbal products with unknown human pharmacology (CB1 Ki = 0.9 nM). Objective: Our goal was to characterize AB-FUBINACA’s metabolism with human hepatocytes incubation and HRMS to identify the best urinary targets. Method: We incubated 10 µM AB-FUBINACA in pooled cryopreserved human hepatocytes at 37oC for 0 (control), 1, and 3 h. Reactions were quenched with cold acetonitrile. Samples were centrifuged at 15,000 g at 4oC and supernatant was stored at -80oC for further analysis. Samples were analyzed on the AB Sciex TripleTOF® 5600+ HRMS with a TOF survey scan followed by information-dependent acquisition product ion scan using ion intensity of 500 cps and mass defect filtering (MDF) as criteria, as well as dynamic background subtraction. Data were analyzed with AB Sciex MetabolitePilotTM software utilizing a number of processing algorithms including generic peak finding, MDF, neutral loss, and product ion filtering. Potential metabolites were manually evaluated and assigned a structure, if possible. Results: Almost 80% of parent analyte was unchanged after 1 h, 45% after the 3 h incubation. Two and 7 metabolites were identified after 1 and 3 h, respectively. Two major metabolites, identified at both time points, were the products of carboxamide hydrolysis to butanoic acid (m/z 369.1730) and mono-hydroxylation at the butanoic acid substructure (m/z 385.1667). In addition, their glucuronidated forms also were identified. Other minor metabolites included mono-hydroxylation at the indazole structure (m/z 385.1675), carboxamide hydrolysis to butanoic acid plus mono-hydroxylation at the butyl substructure (m/z 386.1515), and mono-hydroxylation at the indazole substructure and internal hydrolysis (m/z 403.1773). Defluorination at the benzyl ring, and sulfate conjugation were not observed. Conclusion: We present the first in vitro metabolic profile of AB-FUBINACA providing urinary targets for identifying drug intake. We propose targeting metabolites formed by carboxamide hydrolysis to butanoic acid or mono-hydroxylation at the butanoic acid substructure. Given the decrease of parent compound to 45% after 3 h incubation, we also suggest further investigation of metabolite half-lives and intrinsic clearance. Keywords: AB-FUBINACA, Synthetic Cannabinoids, HRMS, Human Hepatocytes Supported by the National Institutes of Health, Intramural Research Program, National Institute on Drug Abuse S-02 The Identification of Primary Metabolites of the Designer Hallucinogen 25I-NBOMe (4-Iodo-2,5- Dimethoxy-N-(2-Methoxybenzyl)-Phenylethylamine) Sara K. Dempsey*1, Justin L. Poklis2, Joseph K. Ritter2, Carl E. Wolf1,3 and Alphonse Poklis1,2,3; Departments of 1Forensic Science, 2Pharmacology & Toxicology, and 3Pathology at Virginia Commonwealth University, Richmond, VA, USA Introduction: In 2010, a novel class of synthetic hallucinogens, the N-methoxybenzyl- methoxyphenylethylamine (NBOMe) derivatives, became readily available on the internet. These derivatives were first synthesized in 2000 and are potent serotonin 2A (5-HT2A) receptor agonists. The 5-HT2A receptor has been closely linked to complex behaviors including working memory and cognitive processes. It has also been implicated in the pathophysiology of affective disorders such as depression and schizophrenia. As a result, the therapeutic effects of atypical antipsychotics are due to antagonism at 5-HT2A receptors. All serotonergic hallucinogens act as 5-HT2A agonists, including the indole derivative lysergic acid diethylamide (LSD). Currently, NBOMe derivatives are sold as powders or on blotter paper with 25I-NBOMe (4-iodo-2,5-dimethoxy- N-(2-methoxybenzyl)-phenylethylamine) being the most commonly reported. Clinical presentations of severe NBOMe intoxication include tachycardia, agitation, hypertension, aggressive/violent behavior, hallucinations and continuous agitation and seizures which can persist for as long as three days. Objective: The identification of 25I-NBOMe metabolites may serve as useful biomarkers in clinical and forensic toxicology. If these metabolites are present in blood, urine and other of specimens in greater abundance and/or have longer half-lives than 25I-NBOMe, they may be valuable biomarkers in postmortem toxicology, driving while impaired testing and all areas of clinical and forensic urine drug testing. Method: The 25I-NBOMe reference material was obtained from Cayman Chemical Company. 25I-NBOMe was incubated in freshly prepared mouse liver microsomes. These in vitro samples were used to generate phase I metabolites. This animal study was approved by the Institutional Animal Care and Use Committee of Virginia Commonwealth University in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. The 25I-NBOMe metabolites formed by the microsomes were identified using a Waters Acquity Xevo TQD LC-MS/MS system. A human serum specimen from a case of 25I-NBOMe intoxication collected approximately 11 hours post ingestion was analyzed for the potential metabolites. Results: Mouse microsomal phase I studies yielded two O-demethylated 25I-NBOMe metabolites and several other metabolites. Mass fragmentation of O-desmethyl-25I-NBOMe indicated that demethylation occurred at either the ortho or the meta position. Chromatographic separation of O-desmethyl-25I-NBOMe indicated the presence of two demethylated metabolites occurring at either the ortho or meta position. The major metabolite appeared to be 4-iodo-2-hydroxy,5-methoxy-N-(2-methoxybenzyl)-phenylethylamine. O-desmethyl-25I-NBOMe was also identified in the serum from the case of clinical intoxication. Conclusion: Given the efficacy and ease of synthesis of 25I-NBOMe and its many derivatives, it is likely that the abuse of these hallucinogens will become more widespread in the future. Therefore this approach to identify biomarkers will be useful in determining NBOMe derivatives in clinical and forensic specimens. Keywords: 25I-NBOMe, 25I-NBOMe Metabolites, O-desmethyl-25I-NBOMe, Microsomes, Phase I Metabolism This project was supported by the National Institute on Drug Abuse (NIDA) Center for Drug Abuse Grant P30DA033934. S-03 Quantification of Cocaine and Metabolites in Exhaled Breath by Liquid Chromatography High Resolution Mass Spectrometry Following Controlled Administration of Intravenous Cocaine Kayla N. Ellefsen*1, 2, Marta Concheiro1, Olof Beck3, David A. Gorelick4, Sandrine Pirard1 and Marilyn A. Huestis1; 1Chemistry and Drug Metabolism, National Institute on Drug Abuse, NIH, Baltimore, MD, USA; 2Program in Toxicology, University of Maryland Baltimore, Baltimore, MD, USA; 3Karolinska Institute, Stockholm, Sweden; 4Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA Introduction: Cocaine is the most widely used illicit stimulant in the United States and Europe. There is increased interest in alternative matrices for identifying drug use in driving under the influence of drugs (DUID), workplace, clinical, and anti-doping programs. Recent studies investigating exhaled breath as an alternative matrix for detecting recent consumption of drugs of abuse, including cocaine, were primarily conducted in drug treatment patients or criminal justice programs, rather than after controlled drug administration. Objective: To validate a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method to quantify cocaine, benzoylecgonine (BE), ecgonine methyl ester (EME), and norcocaine in breath. Breath was collected with the SensAbues device following controlled intravenous (IV) cocaine administration. Method: In this Institutional Review Board (IRB)-approved study, adult cocaine users were administered single 25 mg IV cocaine doses on Days 1, 5 and 10, after providing written informed consent. Exhaled breath specimens were collected over 3 min an hour prior to and 10 min, 0.5, 1, 1.5, 2, 3, 4, 6.5, 9.5, 12.5, and about 21 h post- administration. Filters were extracted with 9 mL 1% formic acid in water, followed by solid-phase extraction on UCT Clean Screen cartridges.
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