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.
Electron-capture gas--liquid chromatographic and reversed-phase high-performance liquid chromatographic assays are described for the quantitation of the compound, 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 the rat and dog 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 analogue, [IV], 3-chloro-4-(9-chloro-5H pyrimido-[5,4-d] [2] benzazepin-7-yl)phenol. This report describes the quantitation of [I] and [II] (major metabolite) in plasma using the above analytical techniques, both in preclinical studies in the dog and in clinical pharmacokinetic studies in man.
D000818:Animals; D014151:Anti-Anxiety Agents; D001552:Benzazepines / Q000097:blood / Q000302:isolation & purification* / Q000378:metabolism; D001711:Biotransformation; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006801:Humans; D007700:Kinetics; D013223:Statistics as Topic
D014151:Anti-Anxiety Agents; D001552:Benzazepines; C039570:9-chloro-7-(2-chlorophenyl)-5H-pyrimido(5,4-d)(2)benzazepine