Human metabolism and basic pharmacokinetic evaluation of AP-238: A recently emerged acylpiperazine opioid.
high resolution mass spectrometry
human liver microsomes
novel synthetic opioid
urinary biomarkers
Journal
Drug testing and analysis
ISSN: 1942-7611
Titre abrégé: Drug Test Anal
Pays: England
ID NLM: 101483449
Informations de publication
Date de publication:
27 Jun 2023
27 Jun 2023
Historique:
revised:
12
06
2023
received:
10
01
2023
accepted:
12
06
2023
medline:
28
6
2023
pubmed:
28
6
2023
entrez:
28
6
2023
Statut:
aheadofprint
Résumé
As a consequence of recently implemented legal restrictions on fentanyl analogs, a new generation of acylpiperazine opioids appeared on the illicit drug market. AP-238 was the latest opioid in this series to be notified by the European Early Warning System in 2020 and was involved in an increasing number of acute intoxications. AP-238 metabolism was investigated to provide useful markers of consumption. For the tentative identification of the main phase I metabolites, a pooled human liver microsome assay was performed. Further, four whole blood and two urine samples collected during post-mortem examinations and samples from a controlled oral self-administration study were screened for anticipated metabolites. In total, 12 AP-238 phase I metabolites were identified through liquid chromatography-quadrupole time-of-flight mass spectrometry in the in vitro assay. All of these were confirmed in vivo, and additionally, 15 phase I and five phase II metabolites were detected in the human urine samples, adding up to a total of 32 metabolites. Most of these metabolites were also detected in the blood samples, although mostly with lower abundances. The main in vivo metabolites were built by hydroxylation combined with further metabolic reactions such as O-methylation or N-deacylation. The controlled oral self-administration allowed us to confirm the usefulness of these metabolites as proof of intake in abstinence control. The detection of metabolites is often crucial to documenting consumption, especially when small traces of the parent drug can be found in real samples. The in vitro assay proved to be suitable for the prediction of valid biomarkers of novel synthetic opioid intake.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.
Références
Gampfer TM, Wagmann L, Park YM, et al. Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine. Arch Toxicol. 2020;94(6):2009-2025. doi:10.1007/s00204-020-02726-1
Giorgetti A, Brunetti P, Pelotti S, Auwärter V. Detection of AP-237 and synthetic cannabinoids on an infused letter sent to a German prisoner. Drug Test Anal. 2022;14(10):1779-1784. doi:10.1002/dta.3351
EMCCDA. Spotlight on … Fentanils and other new opioids. Accessed August 24, 2022. https://www.emcdda.europa.eu/spotlights/fentanils-and-other-new-opioids_en
EMCDDA. European Drug report 2022: Trends and developments. Accessed August 24, 2022. https://www.emcdda.europa.eu/system/files/publications/14644/TDAT22001ENN.pdf
Lamy FR, Daniulaityte R, Barratt MJ, Lokala U, Sheth A, Carlson RG. “Etazene, safer than heroin and fentanyl”: non-fentanyl novel synthetic opioid listings on one darknet market. Drug Alcohol Depend. 2021;225:108790. doi:10.1016/j.drugalcdep.2021.108790
Vandeputte MM, Cannaert A, Stove CP. In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances. Arch Toxicol. 2020;94(11):3819-3830. doi:10.1007/s00204-020-02855-7
Grafinger KE, Wilde M, Otte L, Auwärter V. Pharmacological and metabolic characterization of the novel synthetic opioid brorphine and its detection in routine casework. Forensic Sci Int. 2021;327:110989. doi:10.1016/j.forsciint.2021.110989
Pardo B, Taylor J, Caulkins J, Reuter P, Kilmer B. The dawn of a new synthetic opioid era: the need for innovative interventions. Addiction. 2021;116(6):1304-1312. doi:10.1111/add.15222
Clinton HA, Thangada S, Gill JR, Mirizzi A, Logan SB. Improvements in toxicology testing to identify fentanyl analogs and other novel synthetic opioids in fatal drug overdoses, Connecticut, January 2016-June 2019. Public Health Rep. 2021;136(1_suppl):80S-86S. doi:10.1177/00333549211042829
UNODC. World Drug Rreport 2021. Booklet 3. Accessed April 22, 2022. https://www.unodc.org/res/wdr2021/field/WDR21_Booklet_3.pdf
Di Trana A, Pichini S, Pacifici R, Giorgetti R, Busardò FP. Synthetic Benzimidazole opioids: the emerging health challenge for European drug users. Front Psych. 2022;13:858234. doi:10.3389/fpsyt.2022.858234
EMCCDA. New psychoactive substances: global markets, glocal threats and the COVID-19 pandemic. https://www.emcdda.europa.eu/system/files/publications/13464/20205648_TD0320796ENN_PDF_rev.pdf
De Baerdemaeker KSC, Dines AM, Hudson S, et al. Isotonitazene, a novel psychoactive substance opioid, detected in two cases following a local surge in opioid overdoses. QJM Mon J Assoc Phys. 2022;116(2):hcac039. doi:10.1093/qjmed/hcac039
Krotulski A, Mohr ALA, Logan BK. Trend Report: Q2 2021-NPS Opioids in the United States. 2021Accessed June 22, 2022. https://www.cfsre.org/images/trendreports/2021-Q2_NPS-Opioids_Trend-Report.pdf
Krotulski A, Mohr ALA, Logan BK. Trend Report: Trend Report: Q3 2022 NPS Opioids in the United States. Accessed December 8, 2022. https://www.cfsre.org/images/trendreports/2022-Q3-NPS-Opioids-Trend-Report.pdf
Carrano RA, Kimura KK, Landes RC, McCurdy DH. General pharmacology of a new analgesic-AP-237. Arch Int Pharmacodyn Ther. 1975;213(1):28-40.
Carrano RA, Kimura KK, McCurdy DH. Analgesic and tolerance studies with AP-237, a new analgesic. Arch Int Pharmacodyn Ther. 1975;213(1):41-57.
Irikura T, Masuzawa K, Nishino K, et al. New analgetic agents. V. 1-butyryl-4-cinnamylpiperazine hydrochloride and related compounds. J Med Chem. 1968;11(4):801-804. doi:10.1021/jm00310a022
Resnik K, Brandão P, Alves EA. DARK classics in chemical neuroscience: Bucinnazine. ACS Chem Nerosci. 2021;12(19):3527-3534. doi:10.1021/acschemneuro.1c00522
Zhang C, Han SQGW, Zhao H, Lin S, Hasi WLJ. Detection and quantification of Bucinnazine hydrochloride injection based on SERS technology. Anal Sci Int J Jpn Soc Anal Chem. 2018;34(11):1249-1255. doi:10.2116/analsci.18P158
Krotulski A, Fogarty M, Papsun D, Logan BK. AP-238 Monograph. Accessed August 25, 2022. https://www.cfsre.org/images/monographs/AP-238_111120_CFSRE_Toxicology_Report.pdf
EMCCDA. EDND. Accessed April 22, 2022. https://ednd2.emcdda.europa.eu/ednd/substanceProfiles/1010
Cignarella G, Testa E. 2,6-Dialkylpiperazines. IV. 1-Propionyl-4-substituted cis-2,6-dimethylpiperazines structurally related to the analgetic 8-acyl-3,8-diazabicyclo[3.2.1]octanes. J Med Chem. 1968;11(3):592-594. doi:10.1021/jm00309a039
Fogarty MF, Vandeputte MM, Krotulski AJ, et al. Toxicological and pharmacological characterization of novel cinnamylpiperazine synthetic opioids in humans and in vitro including 2-methyl AP-237 and AP-238. Arch Toxicol. 2022;96(6):1701-1710. doi:10.1007/s00204-022-03257-7
Watanabe S, Vikingsson S, Roman M, Green H, Kronstrand R, Wohlfarth A. In vitro and in vivo metabolite identification studies for the new synthetic opioids Acetylfentanyl, Acrylfentanyl, Furanylfentanyl, and 4-Fluoro-Isobutyrylfentanyl. AAPS J. 2017;19(4):1102-1122. doi:10.1208/s12248-017-0070-z
Giorgetti A, Brunetti P, Haschimi B, Busardò FP, Pelotti S, Auwärter V. Human phase-I metabolism and prevalence of two synthetic cannabinoids bearing an ethyl ester moiety: 5F-EDMB-PICA and EDMB-PINACA. Drug Test Anal. 2022;15(3):299-313. doi:10.1002/dta.3405
Hassanien SH, Layle NK, Holt MC, Zhao T, Iula DM. Cayman NPS Metabolism Monograph https://cdn2.caymanchem.com/cdn/cms/caymanchem/LiteratureCMS/2-methyl%20AP-237%20Metabolomics%20Monograph.pdf
Huppertz LM, Moosmann B, Auwärter V. Flubromazolam-basic pharmacokinetic evaluation of a highly potent designer benzodiazepine. Drug Test Anal. 2018;10(1):206-211. doi:10.1002/dta.2203
Baba S, Morishita S. Studies on drug metabolism by use of isotopes. XVI. Species differences in metabolism of 1-butyryl-4-cinnamylpiperazine hydrochloride. Chem Pharm Bull(Tokyo). 1975;23(9):1949-1954. doi:10.1248/cpb.23.1949
Olah GA, Asensio G, Mayr H. 1-Phenylallyl cations and their rearrangement to indanyl cations in superacidic media. J Org Chem. 1978;43(8):1518-1520. doi:10.1021/jo00402a006
Di Trana A, Brunetti P, Giorgetti R, et al. In silico prediction, LC-HRMS/MS analysis, and targeted/untargeted data-mining workflow for the profiling of phenylfentanyl in vitro metabolites. Talanta. 2021;235:122740. doi:10.1016/j.talanta.2021.122740
Weinshilboum R. Pharmacogenetics of methylation: relationship to drug metabolism. Clin Biochem. 1988;21(4):201-210. doi:10.1016/s0009-9120(88)80002-x
Brunetti P, Lo Faro AF, Di Trana A, et al. β’-Phenylfentanyl metabolism in primary human hepatocyte incubations: identification of potential biomarkers of exposure in clinical and forensic toxicology. J Anal Toxicol. 2022;46(9):bkac065. doi:10.1093/jat/bkac065
Morishita SI, Baba S, Nagase Y. Studies on drug metabolism by use of isotopes XX: ion cluster technique for detection of urinary metabolites of 1-butyryl-4-cinnamylpiperazine by mass chromatography. J Pharm Sci. 1978;67(6):757-761. doi:10.1002/jps.2600670606
Concheiro M, Chesser R, Pardi J, Cooper G. Postmortem toxicology of new synthetic opioids. Front Pharmacol. 2018;9:1210. doi:10.3389/fphar.2018.01210
Pérez-Mañá C, Papaseit E, Fonseca F, Farré A, Torrens M, Farré M. Drug interactions with new synthetic opioids. Front Pharmacol. 2018;9:1145. doi:10.3389/fphar.2018.01145