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This service is more advanced with JavaScript available, learn more at http: Unfortunately, no human metabolism data are currently available, making it challenging to confirm their intake. The present study aims to identify appropriate analytical markers by investigating FDU-PB and FUB-PB metabolism in human hepatocytes and confirm the results in authentic urine specimens. Metabolite identification in hepatocyte samples and urine specimens was accomplished by high-resolution mass spectrometry using information-dependent acquisition. Synthetic cannabinoids SC are agonists at endogenous cannabinoid CB 1 and CB 2 receptors and were initially synthesized as pharmacological probes for investigating the endocannabinoid system and developing potential therapeutic compounds 1 , 2. Since the mids, SC are abused due to psychoactive effects 3 , which has resulted in increased numbers of emergency room visits due to psychotic episodes, kidney failure, stroke, myocardial infarctions, and even occasional deaths 4 , 5 , 6 , 7. A total of SC were scheduled in Japan as narcotics or designated substances as of April 9. Despite regulations, clandestine laboratories continuously produce structurally diverse compounds to circumvent scheduling legislation. FUB-PB is the fluorobenzyl analog of PB, maintaining the core structure of an indole ring system linked to a quinoline by an ester group, but with the pentyl side chain replaced by a para-fluorobenzyl substituent FUB. The only available data about their effects are found in drug user forums on the internet, for instance, www. However, we should be cautious with these data because users are frequently unaware of what compounds they are taking. To date, all investigated SC are extensively metabolized in humans and are predominantly excreted as metabolites in urine 16 , 17 , 18 , complicating detection as metabolites are initially unknown. Since urine is the most common matrix in clinical, sport doping, or roadside testing, knowledge of human metabolism is essential for developing effective urine testing methods to verify FDU-PB and FUB-PB consumption. However, due to the lack of pharmacology, toxicity, and safety data, controlled human pharmacokinetic studies are not yet possible. Human hepatocytes were selected, rather than human liver microsomes HLM , to better simulate a physiological liver environment 20 , Two urine samples collected from individuals suspected of driving under the influence of drugs also were analyzed to assess utility of our in vitro conclusions. The most dominant human hepatocyte metabolites were compared to urinary metabolites. The identified optimal urinary markers can be incorporated into screening methods for documenting SC intake, can assist associating observed adverse events with the causative substances, and can provide reference standard manufacturers with the most critical metabolites for their synthesis efforts. Acetonitrile and ethyl acetate were purchased from Sigma-Aldrich St. HLM metabolic stability assays were performed in the same manner as in our previous manuscripts 19 , Mobile phases were 0. Ion source parameters were as follows: Microsomal intrinsic clearance was scaled to whole-liver dimensions yielding intrinsic clearance CL int. Human hepatic clearance CL H and extraction ratio ER were calculated without considering plasma protein binding. Hepatocyte incubation was performed as previously described 19 , Samples were thawed and vortexed thoroughly. Fifteen microliters of reconstituted solution was injected for analysis. Gradient elution was performed with 0. HPLC eluent was diverted to waste before 2. The mass spectrometer was automatically calibrated every three injections. Acquired data were processed with MetabolitePilot version 1. Special attention was given to phase II metabolites that are susceptible to significant in-source fragmentation. These two urine specimens were not from human experimental investigations. Specimens were anonymized and de-identified prior to shipment to our laboratory for analysis. These specimens are exempt from IRB approval as they are anonymized and do not fall under human experimental investigations. The corresponding blood sample for urine case 1 contained 0. Urine samples were prepared with and without enzymatic hydrolysis as described previously 18 , Data acquisition and processing were the same as for hepatocyte samples; all four data mining algorithms were utilized and the search was not restricted to only metabolites previously identified in hepatocytes. The inserts are the expanded chromatograms of early eluted minor metabolites. M1 eluted early at 3. Direct glucuronidation of M7 generated M5. M5 eluted at 4. Three hydroxylated M7 metabolites were observed, i. Therefore, we propose the hydroxylation to be on the indole moiety. A glucuronide of hydroxylated M7 metabolite, M3, was detected at 4. In total, 4 phase I and 3 phase II metabolites were detected in human hepatocytes Fig. An overview of the metabolic pathway is shown in Fig. Sequential hydroxylation or glucuronidation metabolites from M7 were also the same Fig. M8 eluted early at 1. Ideally, intense metabolites that are specific for each parent compound should be targeted in forensic drug testing. In our study, the p -fluorobenzyl moiety was metabolically stable in the hepatocyte incubation and in vivo , with no biotransformation identified. Ester hydrolysis was the primary biotransformation for both compounds. Naphthol sulfate and quinolinol glucuronide were specifically investigated, but were not observed. Urine is the most common matrix for drug detection and screening due to easy collection, adequate specimen volume, and higher drug concentrations compared to blood producing prolonged detection windows, hence, the importance of identifying urinary metabolites. In our study, we analyzed two urine specimens collected from individuals suspected of driving under the influence of drugs. Similar to the metabolic profile in the hepatocyte samples, M7 also was the predominant metabolite in both urine specimens. The abundance ratio of M6 to M7 in urine 1 is different from that in urine 2; this may be attributed by various factors, such as different collection time points and individual variability in drug-metabolizing enzyme activities 19 , 22 , Definitively identifying the substance consumed is required for forensic testing in some jurisdictions and is difficult when identical metabolites arise from both a scheduled and non-scheduled compound. Definitive differentiation of FDU-PB from FUB-PB intake would require identification of the parent compound in the blood or oral fluid, and the windows of detection of the potent parent compounds in these matrices are expected to be short based on their metabolic stability and low dosage. Hepatocytes are more representative of the physiological liver environment containing all phase I and II drug-metabolizing enzymes, cofactors such as NADPH , and drug transporters 21 , 37 , 38 , In addition, compounds must penetrate across cell membranes before being metabolized, which is not the case for HLM. The hepatocyte incubation model has proven to be successful in predicting in vivo human major metabolites. Molecular Discovery kindly provided the MetaSite software. Research Article First Online: Proliferation of novel psychoactive substances NPS is a global challenge; identifying NPS intake and associating specific adverse effects with the causative agent requires rapid elucidation of NPS and their major urinary metabolites because SC are usually extensively metabolized and the parent drug is rarely present in urine Open image in new window. Metabolite Profiling in Human Hepatocytes Hepatocyte incubation was performed as previously described 19 , All fragments were used as diagnostic ions for metabolite elucidation as similar cleavage patterns could be expected. An overview of the biotransformation pathway is shown in Fig. Metabolite elucidation will be explained as follows. As shown in Fig. Glucuronide conjugates M3 and M5 were predominant metabolites. Urinary Metabolites for Documenting FDU-PB and FUB-PB Intake Urine is the most common matrix for drug detection and screening due to easy collection, adequate specimen volume, and higher drug concentrations compared to blood producing prolonged detection windows, hence, the importance of identifying urinary metabolites. Design, synthesis and pharmacology of cannabimimetic indoles. Bioorg Med Chem Lett. First metabolic profile of XLR, a novel synthetic cannabinoid, obtained by using human hepatocytes and high-resolution mass spectrometry. Acute toxicity due to the confirmed consumption of synthetic cannabinoids: Spice drugs are more than harmless herbal blends: Prog Neuropsychopharmacol Biol Psychiatry. Synthetic cannabinoid and marijuana exposures reported to poison centers. Cardiotoxicity associated with the synthetic cannabinoid, K9, with laboratory confirmation. Am J Emerg Med. Metabolism of synthetic cannabinoids PB and its 5-fluoro analog, 5F-PB, by human hepatocyte incubation and high-resolution mass spectrometry. New psychoactive substances in Europe. Chemical analysis of a benzofuran derivative, 2- 2-ethylaminopropyl benzofuran 2-EAPB , eight synthetic cannabinoids, five cathinone derivatives, and five other designer drugs newly detected in illegal products. Synthetic cannabinoids as designer drugs: Identification and analytical data. The emergence of synthetic cannabinoids in Mayotte. Detection of urinary metabolites of AM and UR, two novel synthetic cannabinoids. Nontargeted SWATH acquisition for identifying 47 synthetic cannabinoid metabolites in human urine by liquid chromatography-high-resolution tandem mass spectrometry. Bioactivation of 3-n-butylphthalide via sulfation of its major metabolite 3-hydroxy-NBP: The pivotal role of hepatocytes in drug discovery. Metabolic characterization of AH, a synthetic opioid designer drug: Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development. An automated liquid chromatography-mass spectrometry process to determine metabolic stability half-life and intrinsic clearance of drug candidates by substrate depletion. Assay Drug Dev Technol. The use of human hepatocytes to select compounds based on their expected hepatic extraction ratios in humans. Synthetic cannabimimetic agents metabolized by carboxylesterases. Metabolites of 5F-AKB, a synthetic cannabinoid receptor agonist, identified in human urine and liver microsomal preparations using liquid chromatography high-resolution mass spectrometry. High-resolution mass spectrometry for characterizing the metabolism of synthetic cannabinoid THJ and its 5-fluoro analog THJ after incubation in human hepatocytes. Quinoline, quinazoline and acridone alkaloids. Conjugation metabolism of acetaminophen and bilirubin in extrahepatic tissues of rats. Mechanistic studies on the absorption and disposition of scutellarin in humans: Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Metabolism and pharmacokinetics of morinidazole in humans: Present status of the application of cryopreserved hepatocytes in the evaluation of xenobiotics: Huestis 1 Email author 1. Cite article How to cite? Cookies We use cookies to improve your experience with our site.
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