Disposition of hexobarbitone in healthy man: kinetics of parent drug and metabolites following oral administration.

Abstract

1 Hexobarbitone plasma kinetics were determined in six healthy volunteers, who received 500 mg hexobarbitone orally. In addition urinary excretion rate and cumulative excretion were measured of its three major metabolites: 3'-hydroxyhexobarbitone, 3'-ketohexobarbitone and 1,5-dimethylbarbituric acid. 2 The mean plasma elimination half-life of hexobarbitone was 3.7 + 0.9 h (n = 6). Assuming complete absorption, the volume of distribution and the metabolic clearance were 81.3 + 20.5 1 and 16.4 + 2.9 1/h, respectively. The mean maximal plasma concentration was 7.1 + 2.1 ,ug/ml and was reached 1.2 + 0.4 h after drug administration. 3 3'-Hydroxyhexobarbitone and 3'-ketohexobarbitone, which are products of allylic side-chain oxidation of hexobarbitone, were excreted in 24 h to the extent of 4.7 + 1.3 and 32.1 + 11.9% of the dose, respectively. In the same period, 1,5-dimethylbarbituric acid, which is the end product of the epoxide-diol pathway, was excreted to 18.0 + 7.8% of the dose. The ratio of the sum of 3'-hydroxyand 3'-ketohexobarbitone vs 1,5-dimethylbarbituric acid excreted varied with time and amounted ultimately in 24 h urine to 2.3 + 1.0. 4 The half-lives of 3'-hydroxyhexobarbitone and 1,5-dimethylbarbituric acid, calculated from their renal excretion rate curves, amounted 5.2 + 0.9 and 6.6 + 1.3 h and were significantly longer than the half-life of hexobarbitone in plasma. The half-life of 3'-ketohexobarbitone was 4.2 + 0.8 h. The maximum excretion rate of 1 ,5-dimethylbarbituric acid was reached at 7.7 + 1.0 h after administration of hexobarbitone. 3'-Hydroxy-and 3'-ketohexobarbitone were excreted with a maximal rate at 2.2 ± 0.8 and 2.8 + 0.4 h respectively.

Disposition of allylic oxidation pathway metabolites of racemic hexobarbital in the rat

“…Apparently, the epoxide-diol pathway as described for HB( -) might not be restricted to HB alone. In fact, this might explain the observation that after HB administration to man, the urinary excretion rate of DMBA takes 8 hours to reach its maximum (13).…”