| Popis: |
The absorption, distribution, excretion and metabolism were investigated after a single oral (3 mg/kg) or intravenous (1 mg/kg) administration of 14C-taltirelin to male rats and dogs. 1. The extent of absorption calculated from the ratio of urinary excretion after or al and intravenous administration of 14C-taltirelin was 9 and 21% of the dose in rats and dogs. The intestinal absorption ratio in non-fasted rats decreased by 38% compared with that in fasted rats. 2. After oral administration to rats, the plasma level of radioactivity reached the maximum level of 157 ng eq./ml at 1 hr after dosing and then decreased with a half-life of 119 min. After oral administration to dogs, the plasma level of radioactivity reached the maximum level of 508 ng eq./ml at 1.5 hr and then decreased with a half-life of 146 min. The values of bioavailability in rats and dogs were 3.9 and 18.5%, respectively. 3. The ratios of plasma protein binding of radioactive substances in rats and dogs were below 12% both under the in vivo and in vitro conditions. 4. Radioactivity levels afte r oral administration to rats reached a peak at 30 min to 3 hr in most tissues and were high in the liver, kidney, spleen, lung, blood and skin, except for gastrointestinal tract. But at 24 hr radioactivity levels in these tissues decreased remarkably. Radioactivity level in the brain, a target organ of pharmacological effect, was low and decreased slowly. 5. In both rats and dogs, most of the dose wa s excreted within 48 hr after dosing and the absorbed 14C-taltirelin was excreted mainly in urine. 6. Radioactivity excreted in bile within 24 hr was 1.7 and 5.7% of the dose after oral and intravenous administration to rats, respectively. 7. Two metabolites, (−)-N-[(S)-hexahydro-1-methyl-2, 6-dioxo-4-pyrimidinyl carbonyl]-L-histidyl-L-proline (“Acid”) and (S)-hexahydro-1-methyl-2, 6-dioxo-4-pyrimidinecarboxylic acid (“MDOA”), together with unchanged taltirelin were detected in plasma and urine of both rats and dogs. |
