Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

Wohlfarth, Ariane; Castaneto, Marisol S.; Zhu, Mingshe; Pang, Shaokun; Scheidweiler, Karl B.; Kronstrand, Robert; Huestis, Marilyn A.

doi:10.1208/s12248-015-9721-0

Cited by 96 publications

(164 citation statements)

References 27 publications

Supporting

Mentioning

144

Contrasting

Order By: Relevance

“…This might be attributed to electron cloud distribution differences between indole and indazole rings. Likewise, no indazole-hydroxylated metabolites were observed for AKB-48 and AB-PINACA (19,34 ). Both AM-2201 and THJ-2201 underwent oxidative defluorination with subsequent carboxylation and glucuronidation (11,16 ).…”

Section: Thj-018 and Thj-2201 Metabolism Compared With Jwh-018 And Ammentioning

confidence: 93%

“…Fragments m/z 229.0979 and 85.0644 indicated pentyl chain carbonylation. Intense m/z 273.1017 betrays 1Ј-carbonylation, in which case the amido bond cleaves easily (5,19,26 ). M13 was the most lipophilic metabolite, eluting at 16.55 min.…”

Section: '-Hydroxylation and Further Oxidation And Glucuronidationmentioning

confidence: 99%

“…However, for THJ-2201, we detected F26 (5Ј-OH-THJ-018) and F18 (5Ј-OH-THJ-018 glucuronide) only after oxidative defluorination. Oxidative defluorination also was the primary metabolic pathway for fluorinated SC, such as AM-2201 (16 ), 5F-AB-PINACA (19 ), , and 5F-PB-22 (36 ), and it dominated THJ-2201 metabolism. F26 and F18 have retention times and spectra identical to those of M8 and M4, respectively.…”

Section: Thj-018 and Thj-2201 Shared Metabolitesmentioning

confidence: 99%

“…Metabolites identified with human hepatocytes can serve as useful markers for identifying novel SCs (19 ). Recent increases in drug-related emergency visits have been linked to new novel psychoactive substances (NPSs) (20 ).…”

mentioning

confidence: 99%

See 3 more Smart Citations

High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes

Diao

Wohlfarth

Pang³

et al. 2016

Clinical Chemistry

Self Cite

View full text Add to dashboard Cite

BACKGROUND Despite increasing prevalence of novel psychoactive substances, no human metabolism data are currently available, complicating laboratory documentation of intake in urine samples and assessment of the drugs' pharmacodynamic, pharmacokinetic, and toxicological properties. In 2014, THJ-018 and THJ-2201, synthetic cannabinoid indazole analogs of JWH-018 and AM-2201, were identified, with the National Forensic Laboratory Information System containing 220 THJ-2201 reports. Because of numerous adverse events, the Drug Enforcement Administration listed THJ-2201 as Schedule I in January 2015. METHODS We used high-resolution mass spectrometry (HR-MS) (TripleTOF 5600+) to identify optimal metabolite markers after incubating 10 μmol/L THJ-018 and THJ-2201 in human hepatocytes for 3 h. Data were acquired via full scan and information-dependent acquisition triggered product ion scans with mass defect filter. In silico metabolite predictions were performed with MetaSite and compared with metabolites identified in human hepatocytes. RESULTS Thirteen THJ-018 metabolites were detected, with the major metabolic pathways being hydroxylation on the N-pentyl chain and further oxidation or glucuronidation. For THJ-2201, 27 metabolites were observed, predominantly oxidative defluorination plus subsequent carboxylation or glucuronidation, and glucuronidation of hydroxylated metabolites. Dihydrodiol formation on the naphthalene moiety was observed for both compounds. MetaSite prediction matched well with THJ-018 hepatocyte metabolites but underestimated THJ-2201 oxidative defluorination. CONCLUSIONS With HR-MS for data acquisition and processing, we characterized THJ-018 and THJ-2201 metabolism in human hepatocytes and suggest appropriate markers for laboratories to identify THJ-018 and THJ-2201 intake and link observed adverse events to these new synthetic cannabinoids.

show abstract

Section: Thj-018 and Thj-2201 Metabolism Compared With Jwh-018 And Ammentioning

confidence: 93%

Section: '-Hydroxylation and Further Oxidation And Glucuronidationmentioning

confidence: 99%

Section: Thj-018 and Thj-2201 Shared Metabolitesmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes

Diao

Wohlfarth

Pang³

et al. 2016

Clinical Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The hepatocyte incubation model was successful in our previous studies for identifying appropriate markers for AB-FUBINACA (19), AB-PINACA (22), and AH-7921 (23), among others. 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.…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Human Metabolism of Synthetic Cannabinoids FDU-PB-22 and FUB-PB-22

Diao

Scheidweiler

Wohlfarth

et al. 2016

AAPS J

Self Cite

View full text Add to dashboard Cite

Abstract. In 2014, FDU-PB-22 and FUB-PB-22, two novel synthetic cannabinoids, were detected in herbal blends in Japan, Russia, and Germany and were quickly added to their scheduled drugs list. 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-22 and FUB-PB-22 metabolism in human hepatocytes and confirm the results in authentic urine specimens. For metabolic stability, 1 μM FDU-PB-22 and FUB-PB-22 was incubated with human liver microsomes for up to 1 h; for metabolite profiling, 10 μM was incubated with human hepatocytes for 3 h. Two authentic urine specimens from FDU-PB-22 and FUB-PB-22 positive cases were analyzed after β-glucuronidase hydrolysis. Metabolite identification in hepatocyte samples and urine specimens was accomplished by high-resolution mass spectrometry using information-dependent acquisition. Both FDU-PB-22 and FUB-PB-22 were rapidly metabolized in HLM with half-lives of 12.4 and 11.5 min, respectively. In human hepatocyte samples, we identified seven metabolites for both compounds, generated by ester hydrolysis and further hydroxylation and/or glucuronidation. After ester hydrolysis, FDU-PB-22 and FUB-PB-22 yielded the same metabolite M7, fluorobenzylindole-3-carboxylic acid (FBI-COOH). M7 and M6 (hydroxylated FBI-COOH) were the major metabolites. In authentic urine specimens after β-glucuronidase hydrolysis, M6 and M7 also were the predominant metabolites. Based on our study, we recommend M6 (hydroxylated FBI-COOH) and M7 (FBI-COOH) as suitable urinary markers for documenting FDU-PB-22 and/or FUB-PB-22 intake.

show abstract

UPLC‐HR‐MS/MS‐based determination study on the metabolism of four synthetic cannabinoids, ADB‐FUBICA, AB‐FUBICA, AB‐BICA and ADB‐BICA, by human liver microsomes

Liu

et al. 2017

Biomedical Chromatography

View full text Add to dashboard Cite

Since 2012, several cannabimimetic indazole and indole derivatives with valine amino acid amide residue have emerged in the illicit drug market, and have gradually replaced the old generations of synthetic cannabinoids (SCs) with naphthyl or adamantine groups. Among them, ADB-FUBICA [N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indole-3-carboxamide], AB-FUBICA [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indole-3-carboxamide], AB-BICA [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-benzyl-1H-indole-3-carboxamide] and ADB-BICA [N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-benzyl-1H-indole-3-carboxamide] were detected in China recently, but unfortunately no information about their in vitro human metabolism is available. Therefore, biomonitoring studies to screen their consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated their phase I metabolism by incubating with human liver microsomes, and the metabolites were identified by ultra-performance liquid chromatography-high resolution-tandem mass spectrometry. Metabolites generated by N-dealkylation and hydroxylation on the 1-amino-alkyl moiety were found to be predominant for all these four substances, and others which underwent hydroxylation, amide hydrolysis and dehydrogenation were also observed in our investigation. Based on our research, we recommend that the N-dealkylation and hydroxylation metabolites are suitable and appropriate analytical markers for monitoring their intake.

show abstract

Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

Cited by 96 publications

References 27 publications

High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes

High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes

In Vitro and In Vivo Human Metabolism of Synthetic Cannabinoids FDU-PB-22 and FUB-PB-22

UPLC‐HR‐MS/MS‐based determination study on the metabolism of four synthetic cannabinoids, ADB‐FUBICA, AB‐FUBICA, AB‐BICA and ADB‐BICA, by human liver microsomes

Contact Info

Product

Resources

About