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 micrograms/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′‐hydroxy‐ and 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. 1983 The British Pharmacological Society