Etorphine pharmacokinetics in the rat: experimental data and mathematical model.

Rats were injected i.v. with 3H-etorphine (200 ng/Kg). At least 85% of the dose was cleared from the blood in the first 2 min. Blood levels continued to fall slowly from about 5% of the administered dose after 15 min to less than 2% after 3 hours. Although more than 15% of the dose was found in the liver and kidney after 15 min, labeled material did not further accumulate in these organs, but decreased to about 3% after 3 hours. The concentration of labeled material (dpm/mg tissue) in cerebellum was less than half that attained in other brain regions at early time points, probably reflecting the low number of opiate receptors in this region. After 2 hours, however, there was little difference between cerebellum and other brain regions. The highest brain concentrations observed were at the earliest time point examined (7 min). An open four compartment kinetic model was constructed to fit the data for etorphine concentrations in (i) plasma, (ii) cerebellum, and (iii) brain (excluding cerebellum). The model has 3 spatial compartments: plasma, brain, and all tissues other than brain. Etorphine in brain occupies either of 2 functional compartments: one representing receptor-bound ligand and the other, the sum of free and nonspecifically bound ligand. The dissociation rate constant for etorphine in vivo obtained by fitting model equations to data was 0.06 min-1, similar to that obtained in vitro in the presence of 150 mM sodium ion.