A gas chromatography/mass spectrometry (GC/MS) methods were established for metabolites of HY-770. Then, the disposition of the metabolites in rats, the species differences, pathways and mechanism of the metabolism were studied.
1. The GC/MS assay methods for the metabolites of HY-770, M2, M3, M4 (erythro and threo), M6 and M8, in the serum, urine, bile and tissues were established.
2. After oral administration of HY-770 (50mg/kg) to rats, the unchanged HY-770 in the serum or liver was quickly decreased and the metabolites increased correspondingly. M2 showed highest concentration among the metabolites, followed by M8, M6. On the other hand, the unchanged HY-770 was highly distributed into the brain, which is the target organ, than any other metabolite.
3. The reason why the gradually decrease of the blood radioactivity until ihour after intravenous administration of ¹⁴C-HY-770 to rats is the delayed production of the metabolites accounting for most of the radioactivity.
4. After oral administration of HY-770 to rats, the half of the excreted amounts into urine or bile was the known metabolites (free+conjugates) .
5. In rats and dogs, M2 and M6, formed by the oxidation, were mainly excreted into urine. On the other hand, M4, formed by the ketone reduction, was a main metabolite in rabbits and human. The species differences in the metabolism were observed.
6. The metabolic pathways of HY-770 were confirmed by the experiments of in vitro and the administrations of the authentic metabolites. At the first step, HY-770 is oxidized by cytochrome P-450 at the ethyl side chain or reduced by ketone reductase at the ketone group, followed by the successive and respective metabolism.
7. When metabolism of HY-770 was studied using rat liver S-9, the product stereoselectivity was observed in the ketone reduction.

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The absorption, distribution, metabolism and excretion of ¹⁴C-semotiadil fumarate (¹⁴C-SD3211) were studied in rats after oral (dose ; 10mg/kg) or intravenous (1 mg/kg) single administration.
1. Concentration of radioactivity in the plasma reached the maximum level of 0.26μg/ml at 1 hr after oral administration and decreased with the half-life of 6.4hr. Concentration of SD-3211 in the plasma reached the maximum level of 0.13μg/ml at lhr, and decreased with the half-life of 3.5hr.
2. Maximum levels of radioactivity in most of tissues were reached at 2 ?? 6hr after oral administration, and high levels of radioactivity were observed in the liver, lung, kidney and harderian gland. At 96hr after oral administration, the levels in every tissue were very low compared with the maximum level.
3. Within 96hr, excretion of radioactivity was about 1.2% and 93.8% of the dose in urine and feces after oral administration, respectively. Similar excretion pattern was observed after intravenous administration, where 5.6% and 93.0% of the dose was excreted to urine and feces.
4. Within 48hr, biliary excretion of radioactivity was 87.3% of the dose after oral administration, and was 88.6% after intravenous administration.
5. In the plasma, lung and kidney, unchanged form was found about 37 ?? 58%, within 6hr after oral administration. But, in liver, unchanged form was minor component. In urine, feces and bile, unchanged form were scarcely detected.

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The absorption, distribution, excretion and metabolism of CGS 14824 A were studied in rats after single administration of ¹⁴C-CGS 14824 A and ¹⁴C-CGS 14831.
1. After oral administration of ¹⁴C-CGS 14824 A at dose of 3mg/kg to fasting male rats, the radioactivity in the plasma reached C_max of 1993ng eq./ml at 10min and the elimination half-lives were 0.37hr (20min ?? 2hr) and 10hr (4 ?? 12hr). In the case of non-fasting male rats, the time of Cmax was delayed by 20min and the level was reduced to 529ng eq./ml ; AUC was not altered by food. Plasma radioactivity increased in proportion to the administered dose with C_max and AUC between 1mg/kg and 10mg/kg. The sex-related differences in the pharmacokinetic profile were not observed.
2. After intravenous or oral administration of ¹⁴C-CGS 14824 A, the extent of absorption was about 100%, but that of ¹⁴C-CGS 14831 was about 6 %.
3. Radioactivity was rapidly and widely distributed to tissues, reaching maximum levels at 10min in most tissues after oral administration of ¹⁴C-CGS 14824 A. A high level of radioactivity was observed in the gastrointestinal tract, followed by liver, kidney and bladder. At 6hr, a high level of radioactivity was found in the lung, exceeding 52 times corresponding plasma levels. At 72hr, the level of radioactivity was reduced in all tissues. Similar distribution characteristic were observed with whole body autoradiography.
4. After oral administration of 3mg/kg of ¹⁴C-CGS 14824 A to fasting male rats, the radioactivity was excreted within 24hr accounted for 27.9 and 68.9% of the dose in urine and feces, respectively, and the total excretion was 99.3% within 72hr. The characteristics of excretion was not changed by administration route, dose and sex. After oral administration to non-fasting male rats, excretion in urine was increased to 37.9% at 72hr.
5. Biliary excretion of radioactivity was 55.8% within 24hr after oral dosing, but entero-hepatic circulation was small.
6. The radioactivity in plasma, lung, liver and kidney was comprised mainly of CGS 14831. Compositions were similar in urine, feces and bile.

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The absorption, distribution, metabolism and excretion of ¹⁴C-CGS 14824 A were studied in male rats durine and after 21 day consecutive oral administration of 3mg/kg/day.
1. The plasma radioactivity at 30min and 8hr after each dose was not affected by repeated administration. The radioactivity in the plasma reached C_max of 789ng eq./ml (20min) and 987ng eq./ml (30min) after the 1st and 21st doses, respectively. After reaching peak concentration, half-lives were similar between the 1st and 21st administration.
2. The radioactivity in tissues at 6hr was not significantly different after the 7th, 14th and 21st doses and 1st dose. After the final administration, high levels of radioactivity were observed in the gastrointestinal tract, liver, bladder and lung. Elimination of radioactivity from tissues was rapid and no accumulation of radioactivity in tissues was observed.
3. The extent of excretion in urine and feces during concecutive oral administration was about 35% and 65%, respectively. The elimination of radioactivity from the body was completed 48hr after the final administration.
4. After repeated oral administration to non-fasting male rats, the radioactivity in the plasma, lung, liver and kidney mainly corresponded to CGS 14831. In the urine and feces, the composition was similar.

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The distribution of radioactivity in the fetus and its transfer into milk were examined after single oral administration of 3mg/kg of ¹⁴C-CGS 14824 A to pregnant or lactating rats.
1. On the whole body autoradiograms on day 12 of gestation, the radioactivity in the fetus was very low at every time point.
2. The whole body autoradiograms taken on day 18 of gestation, revealed a very low radioactivity in the fetus. Radioactivity in the ovary, placenta and uterus was higher than that in plasma of the dam at 6hr. Only low levels of radioactivity were observed in the fetal lung and fetal liver.
3. After oral administration of ¹⁴C-CGS 14824 A to lactating rats, the radioactivity in the milk was not observed 20min after the dosing. The radioactivity remained constant between lhr and 24hr and Cmax was observed at 4 hr. The radioactivity in the milk was less than 39% of the plasma level at every time point. At 48hr, the radioactivity was no longer observed in the milk.

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