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

Hemorrhagic shock (HS) remains a leading cause of trauma-related mortality, primarily due to severe hypovolemia and systemic hypoperfusion. These pathophysiological changes may profoundly affect the pharmacokinetics of fentanyl, an opioid widely used for analgesia in trauma care. Previous studies, predominantly based on fixed-pressure shock models, may not adequately reflect clinically relevant hemodynamic conditions. Therefore, we employed a fixed-volume HS model as an alternative approach to reflect hypovolemia-associated perfusion deficits influencing fentanyl disposition.

This study aimed to evaluate the pharmacokinetics of fentanyl and its primary metabolite, norfentanyl, in an experimental model of fixed-volume HS.

Male Wistar rats were randomly divided into two groups: a control group (C; n = 6) and a fixed-volume hemorrhagic shock group (HS; n = 6). In the HS group, hemorrhage was induced by withdrawal of 30% of the estimated blood volume (EBV) following vascular cannulation. Fentanyl (10 µg/kg) was administered intravenously, and serial blood samples were collected over 60 min. The concentrations of plasma fentanyl and norfentanyl were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin software.

Non-compartmental analysis demonstrated significantly increased systemic exposure to fentanyl in the HS group, reflected by higher area under the concentration-time curve (AUC_0-∞ and AUC_0-t) values, accompanied by a marked reduction in systemic clearance (CL). Mean residence time (MRT) and terminal elimination half-life (t_½λz) were significantly prolonged. Compartmental analysis confirmed a more than two-fold increase in fentanyl exposure, driven primarily by reduced clearance and prolonged elimination. In contrast, peak plasma concentrations (C_max) showed only a borderline increase, and no statistically significant differences were detected in distribution-related parameters. These findings suggest that the major detectable pharmacokinetic changes associated with HS were primarily related to impaired fentanyl elimination. The metabolic conversion ratio (MCR), defined as the ratio of norfentanyl AUC_0-t to fentanyl AUC_0-t, was lower in the HS group (0.117) compared with controls (0.197).

HS significantly alters fentanyl pharmacokinetics in rats by reducing clearance and increasing systemic exposure. The lower norfentanyl-to-fentanyl AUC_0-t ratio suggests that HS may also affect metabolite formation or disposition.