The systemic availabilities of the hepatic high-clearance drug etomidate following oral and rectal administration to rats were determined. The mean curve following intra-arterial administration to another group of rats was taken as a reference. The results showed that the mean rectal systemic availabilities calculated according to the AUC method and the deconvolution method were considerably higher (70.1% and 67.6% respectively) as compared to the mean values following oral administration (4.5% and 9.2% respectively). The deconvolution method gave detailed information about the profiles of the rate and cumulative amount of drug absorbed versus time. It showed that the mean maximal rate of absorption was higher and the time at which this occurred was shorter after rectal (5343 micrograms/hr and 0.13 hr) than after oral (600 micrograms/hr and 0.23 hr) administration. Mean blood elimination half-lives following rectal administration (112.6 min) were longer than that after i.a. administration (61.7 min). The mean half-life of 22.8 min after oral administration should be considered as a distribution half-life. The mean clearance following i.a. administration was 35.2 ml/min (142.7 ml/min/kg), which is higher than hepatic bloodflow and indicates extra-hepatic metabolism. It is concluded that there is a substantial avoidance of hepatic first-pass elimination of etomidate following rectal administration to rats.