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Tritium-labelled (R)-(+) and (S)-(--)-etomidate was injected intravenously in male Wistar rats at four dose levels. Initial plasma clearance was high and the largest part of etomidate was rapidly distributed over those tissues, that had entered in equilibrium with plasma, such as brain, erythrocytes, heart, spleen, lung, kidney, muscle and intestines. Only in subcutaneous fat, testicles and stomach peak levels appeared after 28 minutes. The levels of etomidate, observed in all these tissues varied proportionally with the dose. Although the contents in brain of thw two isomers were comparable, only (R)-(+)-etomidate possesses hypnotic activity. The concentration in brain of (R)-(+)-etomidate, producing hypnotic activity in rats, was 1.50 +/- 0.35 mug/g tissues. Peak levels in liver appeared shortly after administration. Capacity-limited ester hydrolysis in the liver was the main metabolic pathway, yielding a single amphoteric metabolite. The rate of metabolization of (R)-(+)-etomidate was higher than that of the (S)-(--)-isomer. Excretion of the metabolite was mainly with the urine.

The interactions of etomidate and its major metabolite (R 28 141) with plasma proteins were studied by equilibrium dialysis with a multiple cell system. A 4% human serum albumin solution was able to bind 78.5% of the etomidate, and 60.5% of R 25 141, whereas a 1.5% human gamma globulin solution bound etomidate for not more than 3% and did not bind R 28 141 at all. The association constants and free binding energies for the binding of etomidate and R 28 141 to human serum albumin were determined. Plasma protein binding of etomidate was 75.4% in the dog and 76.5% in man; in rat plasma 79.5% of the radioactivity was bound to the plasma proteins, however the etomidate was partly hydrolyzed, even in the presence of sodium fluoride. In the rat 29.7% was distributed to the blood cells, 55.9% bound to plasma proteins and 14.4% was present in plasma water; in the dog the distribution percentages were 42.1%, 43.7% and 14.2% respectively, and in man 37.7%, 47.6% and 14.7% respectively. The major metabolite of etomidate was distributed for 26.3% to the human blood cells, 47.4% was bound to plasma proteins and 26.2% was present in the plasma water; its plasma protein binding amounted to 64.3%. Etomidate was bound at or in the blood cells, whereas R 28 141 was not.

(R)-(+)-etomidate and (S)-(-)-etomidate were found to be metabolized in-vitro by various rat liver homogenization fractions: the 16,000 g supernatant fraction caused a more intensive metabolic breakdown than the microsomal fraction; the 100,000 g supernatant fraction was only slightly active. The metabolism was somewhat more rapid and more extensive for the (R)-(+)-etomidate than for the (S)-(-)-isomer. For both isomers, a dose-dependence was observed: the smaller the substrate concentration, the smaller the relative amount of unmetabolized drug, and the more the rate of metabolic breakdown after a certain incubation time slowed down. Only minor qualitative differences between the metabolic pathways of the two isomers were observed. The main metabolic pathway for the in-vitro metabolism was the hydrolysis of the ethyl ester. Decarboxylation and oxidative N-dealkylation were also observed.

The in vitro plasma protein binding and distribution in blood of fentanyl and three analogues were studied in rats, dogs and healthy volunteers. In human plasma, 84.4% of fentanyl was bound, 92.5% of sufentanil, 92.1% of alfentanil and 93.6% of lofentanil. Plasma protein binding of the four analgesics was independent of their concentration over the whole therapeutic range. Plasma protein binding of alfentanil was much less pH dependent than that of the three other analgesics. Attention was drawn to the possible contribution of the "acute phase' protein alpha 1-acid glycoprotein (alpha 1-AGP), of lipoproteins and of blood cells to the binding of fentanyl and its analogues in blood.