BACKGROUND: PB-22 (1-pentyl-8-quinolinyl ester-1H-indole-3-carboxylic acid) and 5F-PB-22 (1-(5-fluoropentyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid) are new synthetic cannabinoids with a quinoline substructure and the first marketed substances with an ester bond linkage. No human metabolism data are currently available, making it difficult to document PB-22 and 5F-PB-22 intake from urine analysis, and complicating assessment of the drugs' pharmacodynamic and toxicological properties. METHODS: We incubated 10 μmol/l PB-22 and 5F-PB-22 with pooled cryopreserved human hepatocytes up to 3 h and analyzed samples on a TripleTOF 5600+ high-resolution mass spectrometer. Data were acquired via TOF scan, followed by information-dependent acquisition triggered product ion scans with mass defect filtering (MDF). The accurate mass full scan MS and MS/MS metabolite datasets were analyzed with multiple data processing techniques, including MDF, neutral loss and product ion filtering. RESULTS: The predominant metabolic pathway for PB-22 and 5F-PB-22 was ester hydrolysis yielding a wide variety of (5-fluoro)pentylindole-3-carboxylic acid metabolites. Twenty metabolites for PB-22 and 22 metabolites for 5F-PB-22 were identified, with the majority generated by oxidation with or without glucuronidation. For 5F-PB-22, oxidative defluorination occurred forming PB-22 metabolites. Both compounds underwent epoxide formation followed by internal hydrolysis and also produced a cysteine conjugate. CONCLUSION: Human hepatic metabolic profiles were generated for PB-22 and 5F-PB-22. Pentylindole-3-carboxylic acid, hydroxypentyl-PB-22 and PB-22 pentanoic acid for PB-22, and 5'-fluoropentylindole-3-carboxylic acid, PB-22 pentanoic acid and the hydroxy-5F-PB-22 metabolite with oxidation at the quinoline system for 5F-PB-22 are likely the best targets to incorporate into analytical methods for urine to document PB-22 and 5F-PB-22 intake.
BACKGROUND:PB-22 (1-pentyl-8-quinolinyl ester-1H-indole-3-carboxylic acid) and 5F-PB-22 (1-(5-fluoropentyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid) are new synthetic cannabinoids with a quinoline substructure and the first marketed substances with an ester bond linkage. No human metabolism data are currently available, making it difficult to document PB-22 and 5F-PB-22 intake from urine analysis, and complicating assessment of the drugs' pharmacodynamic and toxicological properties. METHODS: We incubated 10 μmol/l PB-22 and 5F-PB-22 with pooled cryopreserved human hepatocytes up to 3 h and analyzed samples on a TripleTOF 5600+ high-resolution mass spectrometer. Data were acquired via TOF scan, followed by information-dependent acquisition triggered product ion scans with mass defect filtering (MDF). The accurate mass full scan MS and MS/MS metabolite datasets were analyzed with multiple data processing techniques, including MDF, neutral loss and product ion filtering. RESULTS: The predominant metabolic pathway for PB-22 and 5F-PB-22 was ester hydrolysis yielding a wide variety of (5-fluoro)pentylindole-3-carboxylic acid metabolites. Twenty metabolites for PB-22 and 22 metabolites for 5F-PB-22 were identified, with the majority generated by oxidation with or without glucuronidation. For 5F-PB-22, oxidative defluorination occurred forming PB-22 metabolites. Both compounds underwent epoxide formation followed by internal hydrolysis and also produced a cysteine conjugate. CONCLUSION:Human hepatic metabolic profiles were generated for PB-22 and 5F-PB-22. Pentylindole-3-carboxylic acid, hydroxypentyl-PB-22 and PB-22 pentanoic acid for PB-22, and 5'-fluoropentylindole-3-carboxylic acid, PB-22 pentanoic acid and the hydroxy-5F-PB-22 metabolite with oxidation at the quinoline system for 5F-PB-22 are likely the best targets to incorporate into analytical methods for urine to document PB-22 and 5F-PB-22 intake.
Authors: Ariane Wohlfarth; Marisol S Castaneto; Mingshe Zhu; Shaokun Pang; Karl B Scheidweiler; Robert Kronstrand; Marilyn A Huestis Journal: AAPS J Date: 2015-02-28 Impact factor: 4.009
Authors: Xingxing Diao; Jeremy Carlier; Mingshe Zhu; Shaokun Pang; Robert Kronstrand; Karl B Scheidweiler; Marilyn A Huestis Journal: Forensic Toxicol Date: 2016-07-06 Impact factor: 4.096
Authors: Richard C Kevin; Timothy W Lefever; Rodney W Snyder; Purvi R Patel; Thomas F Gamage; Timothy R Fennell; Jenny L Wiley; Iain S McGregor; Brian F Thomas Journal: Drug Test Anal Date: 2017-09-28 Impact factor: 3.345
Authors: Xingxing Diao; Karl B Scheidweiler; Ariane Wohlfarth; Shaokun Pang; Robert Kronstrand; Marilyn A Huestis Journal: AAPS J Date: 2016-01-25 Impact factor: 4.009
Authors: Adarsh S Gandhi; Ariane Wohlfarth; Mingshe Zhu; Shaokun Pang; Marisol Castaneto; Karl B Scheidweiler; Marilyn A Huestis Journal: Drug Test Anal Date: 2014-05-14 Impact factor: 3.345
Authors: Jeremy Carlier; Xingxing Diao; Ariane Wohlfarth; Karl Scheidweiler; Marilyn A Huestis Journal: Curr Neuropharmacol Date: 2017-07 Impact factor: 7.363