Abstract
A new hypnotic, 450191-S, is a ring-opened benzodiazepine derivative. It is knownthat the unchanged drug is not detected in plasma and urine after oral administration ofthis drug to humans, and that the metabolites of 450191-S, M-1, M-2, M-A, M-3, and M-4are found in plasma and mainly M-4 is excreted in urine. Some papers have shown thatthe main active metabolites of 450191-S are M-1, M-2, M-A, and M-3.
This paper deals with the pharmacokinetics of 450191-S in healthy volunteers . Plasmahalf-lives of metabolites of 450191-S were M-1, 1.2±0.5hr;M-2, 3.2±0.8hr;M-A, 5.0±1.2hr;M-3, 8.5±1.Ohr;and M-4, 1.7±0.1hr (mean±SD).The half-life of total activemetabolites (the sum of the plasma concentration of M-1, M-2, M-A, and M-3) was 10.5±2.6hr.Plasma concentration of each metabolite after administration of 0.5, 1, 2, 4mgof 450191-S was approximately proportional to the dose. Mean urinary excretion ratio of M-4 was 62. 3% of the dose. Effect of food on the pharmacokinetic parameters was notfound. Plasma concentration of each metabolite after multiple administration showed asimilar time course to the simulation curve calculated using pharmacokinetic parametersestimated from observed plasma concentrations after the first dose. Plasma protein binding ratios measured by ultrafiltration at 37° were M-1, 79.3%;M-2, 81.2-87.5%;M-A, 76.8-78.7%;M-3, 80.8-81.4%;and M-4, 88.9-89.7%.
