Abstract
New synthetic opioids continue to emerge in the illicit market, and among them, fentanyl analogues pose a serious threat to the public health with their abuse and trafficking. We investigated the toxicity of fentanyl analogues on the liver and kidneys mediated by the µ-opioid receptor (MOR). Our study focused on 4-fluoro-isobutyrylfentanyl (4F-iBF), which is classified as a “narcotic” in Japan; structurally similar analogues 4-chloro-isobutyrylfentanyl (4Cl-iBF) and isobutyrylfentanyl (iBF) were also investigated. Rats that were intraperitoneally administered 4F-iBF (5 mg/kg (12.3 μmol/kg)) or iBF (12.3 μmol/kg) displayed hepatic and renal ischemic-like damage, but 4Cl-iBF (12.3 μmol/kg) did milder renal damage only. We found that the agonist activity of 4F-iBF, at MORs was approximately 7.2 times that of 4Cl-iBF, and that pretreatment with MOR antagonist naltrexone (0.8 mg/kg) alleviated liver and kidney injuries caused by 4F-iBF. These results suggested that 4F-iBF might cause ischemic damage to the liver and kidneys, induced by respiratory depression mediated by MORs. Furthermore, to elucidate the metabolism of fentanyl analogues, we investigated the change over time in the amount of 4F-iBF, 4Cl-iBF, iBF (6.15 μmol/kg, respectively), and their respective metabolites in serum after intraperitoneal administration to rats. The results showed that in 24-h post-dose serum, 4Cl-iBF and iBF were substantially eliminated while 4F-iBF remained at about 30% of the maximum level, and each of the N-dephenylethylated metabolites of 4F-iBF, 4Cl-iBF, and iBF was detected in 2-h post-dose serum. The results from this study revealed information on the hepatic and renal toxicities and metabolism related to fentanyl analogues.
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All data related to this study are publicly available upon reasonable request to the corresponding author.
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Acknowledgements
This work was supported by the Pharmaceutical Affairs Section, Health and Safety Division, Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government, Tokyo, Japan. We would like to thank Yuzawa K, Hasegawa Y, and the late Kubo Y for their superb technical support. We are also grateful to personnel in the Animal Care Co., Ltd., and Division of Toxicology at the Tokyo Metropolitan Institute of Public Health for their assistance.
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YO designed the study, performed the research, analyzed the experimental data, wrote the main manuscript text, and prepared Fig. 1 and all tables. MS performed the LC–MS/MS analyses. KM and HT synthesized the reagents. KT contributed to the examinations of histopathology and serum biochemistry. YT contributed to the examinations of histopathology and serum biochemistry and prepared "Fig. 2 and 3." YN contributed to the examinations of histopathology and assisted in writing the manuscript. JN, JS, TS, AI, and TM contributed to administration of the project and assisted in submission of the manuscript. All authors approved for submission of the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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This study received approval from the Animal Experiment Committee of the Tokyo Metropolitan Institute of Public Health (approval nos. 30–16, 19–20, and 20–19). The laboratory animal facilities of the aforementioned institution are accredited by Japan Pharmaceutical Information Center (certification nos. 15–104 and 18–104).
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Ono, Y., Sakamoto, M., Makino, K. et al. Hepatic and renal toxicities and metabolism of fentanyl analogues in rats. Naunyn-Schmiedeberg's Arch Pharmacol 396, 149–159 (2023). https://doi.org/10.1007/s00210-022-02301-8
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DOI: https://doi.org/10.1007/s00210-022-02301-8