Disposition of hexobarbital enantiomers in the rat

The enantiomers of hexobarbital (HB), designated as (+)-HB and (-)-HB, were administered orally to separate groups of rats. Blood concentration-time curves of the parent compounds and the metabolites 3'-hydroxyhexobarbital (OH-HB) and 3'-ketohexobarbital (K-HB) were determined, as well as the cumulative urinary excretion of unconjugated OH-HB, K-HB, and 1,5-dimethylbarbituric acid (DMBA). The t1/2,(+)-HB was 13.4 +/- 0.8 min, and the t1/2,(-)-HB was slightly longer, 16.7 +/- 0.6 min (mean +/- SEM, N = 6). The intrinsic clearance values, CLint,(+)-HB and CLint,(-)-HB, were 2947 +/- 358 and 411 +/- 65 ml min-1 kg-1, respectively. The extraction ratios (E) were 0.94 for (+)-HB and 0.68 for (-)-HB. The t1/2,OH-(+)-HB and t1/2,OH-(-)-HB as calculated from blood data, were nearly the same: 20.0 +/- 2.6 and 22.2 +/- 1.5 min, respectively. Such data could not be established for the K-HB metabolites, since the curves exhibited no clear elimination phase. DMBA was undetectable in blood. The cumulative excretion of the measured metabolites in 24-hr urine was 44.0 +/- 1.8% for (+)-HB and 78.9 +/- 2.9% for (-)-HB, which was predominantly due to a substantial difference in the percentage of K-HB excreted. It is concluded that, to apply HB as a model substrate to assess oxidative enzyme activity, the use of only (-)-HB should be preferred to (+)-HB or (+/-)-HB because of a lower intrinsic clearance and a more complete recovery of oxidized metabolites in urine.