In vivo metabolism of a novel cholecystokinin B (CCK-B) antagonist in rat and dog plasma and rat faeces.

1. The in vivo metabolism of a novel CCK-B antagonist ((+)-N-[1-(adamantane-1-methyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H -1,5-benzodiazepin-3-yl]-N'-phenylurea, GV150013X) was investigated using rat and dog plasma (male and female) and rat faeces samples after administration of GV150013X. 2. Four monohydroxy and four dihydroxy metabolites of GV150013X were identified by comparison with authentic standards using hplc and results from previous in vitro studies. 3. In both rat and dog plasma, GV150013X was converted to one major and other minor metabolites. 4. Qualitatively there is no species or sex differences in the formation of metabolites except that minor metabolite M1 was not detected in dog plasma. 5. Traces of GV150013X and the major metabolite were seen in rat plasma sample 24 h after administration. 6. Hplc with UV and radiochemical detection was used to identify metabolites. Major, non-labelled GV150013X metabolites from rat faeces were collected for characterization by nmr.

Metabolism of a novel CCK-B antagonist in rat, dog and human liver microsomes.

1. The in vitro metabolism of a novel CCK-B antagonist ((+)-N-[1-adamantane-1-methyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H- 1, 5-benzodiazepin-3-yl]N'-phenyl-urea; GV150013X) was investigated using rat, dog and human liver microsomes. 2. Four monohydroxy and four dihydroxy metabolites of GV150013X in rat and man were identified by comparison with authentic standards using HPLC and mass spectrometry. 3. The dihydroxy metabolite M1 was not detected in dog liver microsomes mixtures. 4. The formation of dihydroxylated metabolites proceeds via monohydroxylated metabolites M5 and M8 and not directly from GV150013X. 5. A monohydroxy metabolite M5 was the major metabolite in rat and dog, with M5 and dihydroxy metabolites M2 and M3 major metabolites in man.