Determination of a pyrimido-benzazepine anxiolytic agent and its 5-hydroxy metabolite in whole blood, plasma and urine by gas--liquid chromatography with electron-capture detection and by high-performance liquid chromatography
Puglisi, C.V.; Ferrara, F.J.; de Silva, J.A.
Journal of Chromatography 275(2): 319-333
1983
ISSN/ISBN: 0021-9673 PMID: 6137489 Document Number: 219184
Electron-capture GLC and reversed-phase high-performance liquid chromatographic assays are described for the quantitation of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido [5,4-d] [2]-benzazepine, [I] a member of the benzazepine class of compounds undergoing clinical evaluation as anxiolytic agents. Studies on the biotransformation of I in rats and dogs showed that the compound was metabolized mainly by hydroxylation to yield the 5-hydroxy compound [II] 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]-benzazepin-5-ol (major metabolite) along with the formation of lesser amounts of the N-oxide [III] 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]-benzazepine 3-oxide and the phenolic analog [IV] 3-chloro-4-(9-chloro-5H pyrimido-[5,4-d] [2]benzazepin-7-yl)phenol. The quantitation of I and II (major metabolite) in plasma was performed using the above analytical techniques, both in preclinical studies in dogs and in clinical pharmacokinetic studies in man.