Sex-related pharmacokinetic and pharmacological responses to 4F-Furanylfentanyl

SABRINE BILEL¹Camilla Montesano²Micaela Tirri¹Giorgia Corli¹Marta Bassi¹Nicole Cocita¹Fabiana Di Rosa³Adolfo Gregori³Claudio Trapella⁴Manuel Sergi²Matteo Marti^1*

• ¹Department of Translational Medicine, University of Ferrara, Ferrara, Italy
• ²Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy, Rome, Italy
• ³Carabinieri, Department of Scientific Investigation (RIS), 00191 Rome, Italy, Rome, Italy
• ⁴Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy, Ferrara, Italy

Background: Novel synthetic opioids (NSOs), including a variety of fentanyl analogs (FAs) and emerging non-fentanyl compounds, have been increasingly implicated in overdose fatalities worldwide. Among these, 4-Fluoro-Furanylfentanyl (4F-FUF) is a potent FA with limited in vivo pharmaco-toxicological characterization. This study aimed to (i) evaluate the pharmaco-toxicological effects of 4F-FUF in male and female mice, (ii) determine its pharmacokinetic profile in plasma and tissues of both sexes, and (iii) correlate behavioral and physiological responses with plasma concentrations. Methods: Female and male mice were injected intraperitoneally with 4F-FUF at an effective dose of 5 mg/kg. Behavioral and physiological responses, including sensorimotor, motor, and respiratory parameters, were assessed at multiple time points post-administration. Plasma and tissue samples (brain, heart, liver, spleen, lung, kidney, stomach) were collected to determine 4F-FUF concentrations and pharmacokinetic parameters. Correlations between plasma levels and behavioral or physiological outcomes were analyzed separately by sex. Results: 4F-FUF impaired the sensorimotor and motor responses in females and males. Moreover, the FA induced a persistent antinociception in males with respect to females. The respiratory depression was sudden and more pronounced in male mice. Plasma concentrations of 4F-FUF were higher and persisted longer in males, indicating slower clearance compared to females. This drug was highly distributed in the brain and liver of both sexes. Significant correlations were detected in visual placing, vibrissae responses, spontaneous locomotion and mechanical analgesia in both sexes. Interestingly, respiratory rate was only significantly correlated with plasma concentrations in females, highlighting potential sex-specific differences in the relationship between drug exposure and physiological effects. Conclusion: The findings demonstrate marked sex differences in the behavioral, physiological and pharmacokinetics of 4F-FUF. These results underscore the importance of considering sex differences in assessing the toxicity and risk profiles of novel synthetic opioids.