Hepatic and renal toxicities and metabolism of fentanyl analogues in rats

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 mu-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 mu mol/kg)) or iBF (12.3 mu mol/kg) displayed hepatic and renal ischemic-like damage, but 4Cl-iBF (12.3 mu mol/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 mu mol/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.

Automated summary

New synthetic opioids, particularly fentanyl analogues, present a serious threat to public health due to their abuse and trafficking. This study investigated the toxic effects of fentanyl analogues on the liver and kidneys, focusing on 4-fluoro-isobutyrylfentanyl (4F-iBF). The results revealed that 4F-iBF can cause ischemic damage to the liver and kidneys through mu-opioid receptor-mediated respiratory depression.