Absorption, distribution and excretion of a new thienodiazepine derivative (Y-7131) in rats and mice

Abstract

The synthesis of radioactive 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepine (Y-7131), a new psychotropic agent, is descirbed. The labelled compound was rapidly and completely absorbed following oral administration to rats and mice. The blood levels of radioactivity reached maximum at 0.5 h in rats, and 1 h in mice, respectively, and then declined rapidly with biological half-lives of about 1.5 h in both animals, although the level was higher in mice than in rats. Approximately 45% of the radioactivity in the serum was bound to the serum protein at 1 h after oral administration. The dosed radioactivity was almost completely excreted within 3 days. In rats, more radioactivity was excreted in feces than in urine, while the reverse was noted in mice. An extensive biliary excretion of radioactivity was evidenced in rats after oral dosing. The highest concentrations of radioactivity were found in the liver, kidney, and adrenals, while relatively low levels in the brain of rats. The distribution patterns of radioactivity in mice were similar to those in rats except for the serum and liver. No remarkable accumulation of radioactivity in rat tissues was observed by repeated oral doses of the labelled compound for periods up to 21 days. The metabolic pathways of Y-7131 were qualitatively similar in rats and mice, and one of them was demonstrated to be the hydroxylation at alpha-position in the ethyl side chain.