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

The pharmacokinetics in blood of the major metabolites of hexobarbital (HB), 3'-hydroxyhexobarbital (OH-HB) and 3'-ketohexobarbital (K-HB) were studied in rats. In addition urinary excretion of OH-HB and K-HB and 1,5-dimethylbarbituric acid (DMBA) was determined. Half-lives of OH-HB and K-HB were slightly longer than that of the parent drug. Urinary recovery of OH-HB, K-HB and DMBA following i.a. administration of OH-HB (75%) was more complete than the recovery following i.a. administration of K-HB (52%). Most probably further metabolism of K-HB takes place. Of K-HB, 41% was excreted renally, and 3.4% of K-HB reverted back to OH-HB. Of OH-HB, about 45% was excreted renally, following p.o. or i.a. administration. Since about 10% of both OH-HB and K-HB was converted to DMBA, it seems that the epoxide-diol pathway as proposed for HB also plays a minor role in the metabolism of OH-HB and K-HB. It is further concluded that measuring allylic pathway oxidation metabolites of HB does not improve the usefulness of HB as a model compound in the assessment of the activity of oxidative drug metabolizing activity.