Biosynthesis and Identification of an N-Oxide/N-Glucuronide Metabolite and First Synthesis of an N-O-Glucuronide Metabolite of Lu AA21004

Uldam, Henriette Kold; Juhl, Martin; Pedersen, Henrik; Dalgaard, Lars

doi:10.1124/dmd.111.040428

Cited by 27 publications

(15 citation statements)

References 28 publications

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“…Surprisingly, an uncommon pathway was observed for THJ-2201, i.e., glucuronidation after N-oxidation (F16). N-Oxide glucuronidation is rare, with only sporadic reports (28,30 ). To date, this reaction was not reported for any other SC.…”

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

confidence: 99%

“…F22 was probably an N-oxide rather than a hydroxylated metabolite, under which circumstance it is unlikely to yield high abundance of m/z 249.1026 and 233.1079 simultaneously. Generally, neutral loss of H 2 O, rather than O, is observed between fragment ions of hydroxylated metabolites, whereas loss of O or OH radical is common for N-oxides during fragmentation (27)(28)(29).…”

Section: N-oxide and Further Glucuronidationmentioning

confidence: 99%

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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

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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.

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

confidence: 99%

Section: N-oxide and Further Glucuronidationmentioning

confidence: 99%

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

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“…Vortioxetine reaches peak plasma concentrations of 9, 18 and 33 ng/mL within [7][8][9][10][11] h following the doses of 5, 10 and 20 mg/day, respectively. The absolute bioavailability for oral administration of vortioxetine was found to be 75% [5].…”

Section: Introductionmentioning

confidence: 98%

An UPLC–MS/MS method for the quantitation of vortioxetine in rat plasma: Application to a pharmacokinetic study

Huang

Liang

et al. 2015

Journal of Chromatography B

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“…Lu AA21004-piperazine HBr (Lu AA21004 HBr), benzylic alcohol of Lu AA21004, M0 (benzoic acid of Lu AA21004; Lu AA34443), M4(a) (sulfoxide of Lu AA21004), M8 (4-hydroxy-phenyl of Lu AA21004 sodium salt), and the N-hydroxylated intermediate of Lu AA21004 were prepared at H. Lundbeck A/S as described in supplemental data and by Uldam et al (2011). […”

Section: Methodsmentioning

confidence: 99%

“…The major metabolites in human plasma were the benzoic acid of Lu AA21004, M0 [3-methyl-4-(2-piperazin-1-yl-phenysulfanyl)-benzoic acid (Lu AA34443)], and its glucuronide, M4(b). Other metabolites detected in human plasma were a 4-hydroxy-phenyl metabolite, M8, which is further conjugated to its glucuronide, M3, a sulfoxide, M4(a), and two glucuronides, M11 and M12, of the N-hydroxylated Lu AA21004 [L. Bendahl and L. Dalgaard, unpublished data; Uldam et al (2011)]. The primary metabolites in excreta were the benzoic acid metabolite of Lu AA21004, M0, and its glucuronide conjugate, M4(b), accounting for the vast majority of the dose administered (L. Bendahl and L. Dalgaard, unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Identification of the Cytochrome P450 and Other Enzymes Involved in the In Vitro Oxidative Metabolism of a Novel Antidepressant, Lu AA21004

Hvenegaard¹,

Bang‐Andersen²,

Pedersen³

et al. 2012

Drug Metab Dispos

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ABSTRACT:1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine (Lu AA21004) is a novel antidepressant that is currently in late-stage clinical development for major depressive disorder. In the present study, the metabolism of Lu AA21004 was investigated using human liver microsomes (HLM), human liver S9 fraction, and recombinant enzymes. Lu AA21004 was found in vitro to be oxidized to a 4-hydroxy-phenyl metabolite, a sulfoxide, an N-hydroxylated piperazine, and a benzylic alcohol, which was further oxidized to the corresponding benzoic acid [3-methyl-4-(2-piperazin-1-yl-phenysulfanyl)-benzoic acid (Lu AA34443)]. The formation of the 4-hydroxy-phenyl metabolite was catalyzed by CYP2D6 with some contribution from CYP2C9, whereas the formation of the sulfoxide was mediated by CYP3A4/5 and CYP2A6. CYP2C9 and CYP2C19 were the primary enzymes responsible for formation of the N-hydroxylated metabolite. The benzylic alcohol was formed by CYP2D6 only. The oxidation of the benzylic alcohol to the corresponding benzoic acid of Lu AA21004 was catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase, with some contribution from aldehyde oxidase. CYP2D6 was also capable of catalyzing the formation of the benzoic acid of Lu AA21004; however, its overall contribution to this pathway was negligible. Enzyme kinetic parameters revealed that the rate-limiting step in the formation of the benzoic acid from Lu AA21004 is the formation of the corresponding alcohol. Thus, the intrinsic clearance (V max /K m ) in HLM for metabolism of Lu AA21004 to the benzylic alcohol was 1.13 ؋ 10, whereas the subsequent metabolism of the benzylic alcohol to the benzoic acid of Lu AA21004 is characterized by an intrinsic clearance (V max /K m ) in S9 fraction of 922 ؋ 10 ؊6 l ⅐ min ؊1 ⅐ mg ؊1.

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Biosynthesis and Identification of an N-Oxide/N-Glucuronide Metabolite and First Synthesis of an N-O-Glucuronide Metabolite of Lu AA21004

Cited by 27 publications

References 28 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

An UPLC–MS/MS method for the quantitation of vortioxetine in rat plasma: Application to a pharmacokinetic study

Identification of the Cytochrome P450 and Other Enzymes Involved in the In Vitro Oxidative Metabolism of a Novel Antidepressant, Lu AA21004

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