| Popis: |
The metabolism of NKH477 by the rat liver 9000×g supernatant was investigated. Also the metabolites of NKH477 in plasma, tissue, urine, feces and bile were analyzed after intravenous administration of 14C-NKH477 to rats and dogs or NKH477 to human. 1. The structure of NKH477 and its metabolites in the rat liver 9000×g supernatant was confirmed by comparing with authentic compound using LC/FRIT-FAB-MS. The metabolic pathways of NKH477 were N-demethylation, hydroxylation and intramolecular cyclization. 2. The metabolites of NKH477 in plasma and various tissues were analyzed after a single intravenous administration of 14C-NKH477 to rats. At 15 and 30 min after administration, NKH477 and M-1 (N-demethyl form) were major compounds found in plasma, heart and kidney. At 5 min after administration, various metabolites in the liver were found, suggesting that the liver was main metabolizing organ. 3. The metabolites of NKH477 in urine, feces and bile were analyzed after a single intravenous administration of 14C-NKH477 to rats. Within 24 hr after administration, in urine 0.8% of dose was excreted as NKH477, 2.2% as M-1, 1.7% fraction D containing M-3 (hydroxy form) and M-4 (N-demethyl hydroxy form) and 1.7% as fraction C containing M-5 (intramolecular cyclic form) and M-6 (N-demethyl intramolecular cyclic form). Main metabolite in rat urine was M-1. Within 48 hr after administration, in feces 20.9% of dose was excreted as fraction D, 15.8% as fraction C, and 14.6% as fraction B containing M7 (hydroxy M-5) and M-8 (hydroxy M-6), while the NKH477 and urinary main metabolite M-1 were found in minimal quantities. Within 6 hr after administration, in bile 13.4% of dose was excreted as fraction D, 14.4% as fraction C, and 11.8% as fraction B, and the profile in bile was the same as that in feces. 4. The metabolites of NKH477 in urine and feces were analyzed after a single intravenous administration of 14C-NKH477 to dogs. Within 24 hr after administration, in urine 2.8% of dose was excreted as NKH477, 5.9% as M-1 and 1.3% as fraction D. Main metabolite in dog urine was M-1. Within 72 hr after administration, in feces 20.9% of dose was excreted as fraction D, 9.9% as fraction C, and 6.0% as fraction B, and metabolic profile in dog urine was similar to that in rat urine and feces. 5. The metabolites of NKH477 in urine were analyzed after a single intravenous infusion of NKH477 to healthy volunteers. Within 24 hr after administration, the major compounds in human urine were NKH477 and M-1, and other metabolites were found in trace amount. |
