Sex-related pharmacokinetic and pharmacological responses to 4F-furanylfentanyl.

Background: Novel synthetic opioids (NSOs), including a variety of fentanyl analogs (FAs) and emerging non-fentanyl compounds, have increasingly been implicated in overdose fatalities worldwide. Among these, 4-fluoro-furanylfentanyl (4F-FUF) is a potent FA with limited 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 timepoints post-administration. Plasma and tissue samples (brain, heart, liver, spleen, lung, kidney, and 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 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 than in females. This drug was highly distributed in the brain and liver tissues of both sexes. Significant correlations were detected in visual placing, vibrissae responses, spontaneous locomotion, and mechanical analgesia in both sexes. Interestingly, the 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-specific differences in the behavioral and physiological changes and pharmacokinetics of 4F-FUF. These results underscore the importance of considering sex-specific differences in assessing the toxicity and risk profiles of novel synthetic opioids.