DISPOSITION OF HEXOBARBITAL IN THE RAT - ESTIMATION OF 1ST-PASS ELIMINATION AND INFLUENCE OF ETHER ANESTHESIA

Abstract

The disposition of hexobarbital was studied in rats after i.v. and i.a. [intraarterial] administration. In addition to sleeping times, plasma concentration profiles were measured. No significant differences were found in sleeping times, volumes of distribution, elimination half-lives or systemic clearances between these different routes. The average elimination half-lives were 13.5 .+-. 0.8 (n = 17) and 11.6 .+-. 1.9 min (n = 21) (means .+-. S.E.M. [standard error of the mean]), respectively, whereas the systemic whole blood clearance values were 75.4 .+-. 3.4 (n = 17) and 85.8 .+-. 3.5 ml/min per kg (n = 21)(means .+-. S.E.M.). The values of the latter parameter approach hepatic blood flow in the rat (i.e., 100 ml/min per kg) and therefore the oral availability of hexobarbital was established by comparing areas under plasma concentration time curves, after i.v. and oral administration to the same rat. Oral availability was 36%, which corresponds to an extraction ratio of 64%. The consequences of such a "1st-pass" effect are discussed in view of the use of hexobarbital as a model substrate for measuring drug-metabolizing enzyme activity. Anesthesia as induced by diethyl ether during the experiments resulted in a very significant inhibition of the rate of hepatic metabolism of hexobarbital; the elimination half-life increased by about 50% due to a similar decrease in the systemic clearance. The protein binding of hexobarbital in rat plasma amounted to 51.4 .+-. 1.2% (mean .+-. S.E.M., n = 15) and it was not dependent on the plasma concentration of hexobarbital in the range encountered in vivo.