Pharmacokinetics of repeated, high-dose fentanyl administration in rats

Fentanyl is a potent synthetic opioid widely used as a recreational drug. It is primarily metabolized in the liver to the inactive compound norfentanyl, with only a small fraction excreted unchanged via the kidneys. However, it remains unclear whether repeated high-dose exposure alters its pharmacokinetics (PK) over time. This study evaluated the effects of repeated high-dose fentanyl administration on PK and assessed sex-related differences in metabolism.Male and female Sprague–Dawley rats (n = 19) received intravenous boluses of 100 μg/kg fentanyl twice weekly for five weeks. After the 1st, 5th, and 10th doses plasma concentrations of fentanyl and norfentanyl were measured using ultra-high-performance liquid chromatography - electrospray ionization - tandem mass spectrometry. PK data were analyzed using non-compartmental methods, followed by covariate analysis within a population PK model and a physiologically based PK model to identify underlying physiological factors.Non-compartmental analysis showed significantly lower C max and longer t 1/2 of norfentanyl in females compared to males. Population PK analysis using a two-compartment model confirmed slower fentanyl clearance and reduced norfentanyl formation in females. Repeated dosing led to decreased fentanyl clearance after the 10th exposure. In males, higher muscle volume was inversely correlated with total body clearance, while in females, fat volume correlated positively with total fentanyl exposure.Repeated high-dose fentanyl administration had only modest effects on PK, limited to reduced fentanyl clearance after the final exposure. Pronounced sex differences in fentanyl metabolism were observed with female animals clearing both fentanyl and norfentanyl more slowly and producing less norfentanyl than males.