Abstract
The transport of a new sleep-inducer, 450191-S, and its metabolites, M-1, M-2, M-A, M-3 and M-4, to the brain was examined by the BUI (Brain Uptake Index) method in rats and by comparing the plasma and the brain concentration of the metabolites in mice. 450191-S was not passed to the brain and M-A was hardly passed, but the permeability of M-1, M-2 and M-3 was as high as that of diazepam. The blood-brain barrier (BBB) permeability of these benzodiazepines correlated with the lipid solubility expressed by the Rm value. After oral administration of 450191-S or M-1 to mice, the common major metabolites, M-1, M-2, M-A, M-3 and M-4, were detected in the plasma. At the dose level of 5.5 μmol/kg, M-A showed the highest plasma concentration among the metabolites, but only a low level in the brain. At an increased dose of 55 μmol/kg, M-2 showed the highest concentration in both the plasma and the brain. These results with mice correlated well with the results of BBB permeability in rats. The brain level of M-4 was almost at the background level in spite of a considerable plasma level. The total brain concentration of pharmacologically active metabolites immediately after administration of M-1 rose much faster and to a higher level than after 450191-S administration. These results may explain the pharmacological character of 450191-S.
