Tissue Redistribution of Fentanyl and Termination of Its Effects in Rats

Abstract

The kinetics of fentanyl elimination from plasma suggest its rapid and extensive uptake by tissues. The relationships between tissue and plasma concentration of fentanyl were determined. Six rats injected i.v. with 3H-fentanyl citrate (50 .mu.g/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 (t1/2.alpha. = 8 min, t1/2.beta. = 45 min). Fentanyl uptake by muscle and fat was slower and equilibration with plasma occurred by 120 min. Muscle accumulated 56% of the dose within 5 min, by which time brain fentanyl levels had declined by 90%. Only 6% of the dose was in fat at 5 min but this increased to a maximum of 17% at 30 min. Fentanyl was extensively metabolized; metabolites represented 25% of body 3H-radioactivity at 15 min and 80% at 4 h. The short duration of fentanyl effect is probably 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 may be 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.