Metabolic Fate of NKH477. (4). Metabolism after Intravenous Administration in Rats, Dogs and Human.
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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 <SUP>14</SUP>C-NKH477 to rats and dogs or NKH477 to human.<BR> 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.<BR> 2. The metabolites of NKH477 in plasma and various tissues were analyzed after a single intravenous administration of <SUP>14</SUP>C-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.<BR> 3. The metabolites of NKH477 in urine, feces and bile were analyzed after a single intravenous administration of <SUP>14</SUP>C-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.<BR> 4. The metabolites of NKH477 in urine and feces were analyzed after a single intravenous administration of <SUP>14</SUP>C-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.<BR> 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.
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