Tissue Redistribution of Fentanyl and Termination of Its Effects in Rats

TLDR

Fentanyl is rapidly and extensively taken up by tissues, as indicated by its plasma elimination kinetics. The study aimed to characterize the relationship between tissue and plasma fentanyl concentrations. Six rats received an intravenous 3H‑fentanyl citrate dose and were sacrificed at 1.5–240 min post‑injection, with tissues assayed for unchanged drug and total radioactivity. Fentanyl’s effects peak within 10 s and resolve within 60 min, with rapid brain–plasma equilibration but slower uptake into muscle and fat, extensive hepatic metabolism (80 % of radioactivity as metabolites by 4 h), and ultimate urinary excretion of metabolites, explaining its brief action through redistribution and biotransformation.

Abstract

The kinetics of fentanyl elimination from plasma suggest its rapid and extensive uptake by tissues. The authors determined the relationships between tissue and plasma concentrations of fentanyl. Six rats injected iv with 3H-fentanyl citrate (50 micrograms/kg) were sacrificed at each of the following times: 1.5, 5, 15, 30, 60, 120, and 240 min after injection. Tissues were analyzed for unchanged 3H-fentanyl citrate and for total 3H-radioactivity. Fentanyl effects were evident 10 s after injection; recovery began at 5 min and was complete within 60 min. Fentanyl concentrations in brain, heart, and lung equilibrated with that in plasma before 1.5 min and declined at the same rate (t 1/2 alpha = 8 min, t 1/2 beta = 45 min). Fentanyl uptake by muscle and fat was slower and equilibration with plasma occurred by 120 min. Muscle accumulated 56 per cent of the dose within 5 min by which time brain fentanyl levels had declined by 90 per cent. Only 6 per cent of the dose was in fat at 5 min but this increased to a maximum of 17 per cent at 30 min. Fentanyl was extensively metabolized; metabolites represented 25 per cent of body 3H-radioactivity at 15 min, and 80 per cent at 4 h. The authors conclude that the short duration of fentanyl effect is due to its rapid redistribution from sites of action in the brain to sites of storage (muscle and fat) and biotransformation (liver). The elimination of fentanyl from the body is governed by its reuptake from storage sites and its metabolism in the liver. Most of the dose is ultimately excreted in the form of fentanyl metabolites in urine.