Pharmacokinetics of Fentanyl and Norfentanyl in a Rat Model of Fixed-Volume Hemorrhagic Shock

Hemorrhagic shock is a leading cause of trauma-related mortality and can alter the pharmacokinetics of fentanyl, an opioid commonly used for analgesia in trauma care. This study used a fixed-volume hemorrhagic shock model in Wistar rats, intended to better reflect clinically relevant hypovolemia than prior fixed-pressure models, to evaluate fentanyl and norfentanyl disposition following intravenous administration. Plasma concentrations were quantified by LC-ESI-MS/MS and pharmacokinetic parameters calculated using Phoenix WinNonlin. Hemorrhagic shock significantly increased systemic exposure to fentanyl, driven primarily by reduced clearance and prolonged elimination half-life rather than changes in distribution, and lowered the norfentanyl-to-fentanyl AUC ratio relative to controls. The findings suggest hemorrhagic shock meaningfully impairs fentanyl elimination and may also affect metabolite formation, with implications for dosing in trauma patients.