The absorption and excretion of ¹⁴C-TEI-5103 after single oral (200 mg/kg) or intravenous (10 mg/kg) administration were studied in rats and dogs.
1. After oral administration of ¹⁴C-TEI-5103, the amount absorbed from the gastrointestinal tract was estimated as about 3 % in rats and about 6 % in dogs.
2. After oral administration, the maximum concentration of radioactivity was obtained at 0.5 hr in rats and 1 hr in dogs, and was followed by a biexponential decline with initial biological half-lives (T_1/2) of 0.6 hr in rats and 1.5 hr in dogs. After intravenous administration, the elimination of radioactivity from plasma in both species was rapid and biphasic.
3. After oral administration in rats, 1.6 % of the dose was excreted in the urine and 100.1 % of the dose in the feces, within 72 hr. In dogs, 3.9 % and 94.9 % of the dose was excreted with urine and feces respectively. In both species, most of radioactivity was excreted with urine and feces within 24 hr.
4. The cumulative excretion of radioactivity into bile amounted to 2.8 % and 42.7 % of the dose within 24 hr after oral and intravenous administration, respectively.
5. Protein binding of ¹⁴C-TEI-5103 in vitro was 44-45 % in rat plasma, and 21-23 % in dog plasma. In vivo, plasma protein binding was about 64 % at 0.5 hr after oral administration of ¹⁴C-TEI-5103 to rats.

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The distribution of ¹⁴C-TEI-5103 after single administration (oral: 200 mg/kg, intravenous: 10 mg/kg) and repeated oral administration (200 mg/kg/day) were studied in rats. The passage of radioactivity after oral administration of ¹⁴C-TEI-5103 (200 mg/kg) from mothers into the foetuses and the milk were studied in the pregnant and lactating rats, respectively.
After single oral administration of ¹⁴C-TEI-5103, the radioactivity was high in the gastric wall and intestine, secondly in the liver and kidney of rats. The radioactivity in the other organs and tissues were lower than that in plasma. After intravenous administration, the radioactivty distributed mainly in the liver, intestine and kidney, but extremely low in the brain and spinal cord.
After both administration, the disappearance of radioactivity in the organs and tissues was rapid.
In case of repeated oral administration for 13 days, the radioactivity in the plasma, reached a plateau at least by the 4 th dosing and in the range of 0.9-1.2 times after single administration. The values of the tissue-to-plasma concentration ratio at 1 hr after repeated dose was almost same as that after a single dose. The accumulation in all tissues was very low.
The passage of radioactivity from mothers into the foetuses and the milk in the pregnant and lactating rats, was extremely low.

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Biotransformation of 3-[p-trans-4-aminomethyl-cyclohexylcarbonyl)phenyl]propionic acid hydrochloride (TEI-5103) was studied in rats and dogs.
1) Three metabolites which were related chemically to TEI-5103 were detected in urine; they were identified on a UV spectrum, Chromatograph and Mass spectrum by direct comparison with authentic compounds as follows: 3-[p-(4-carboxycyclohexylcarbonyl)phenyl]propionic acid (M-1), p-(4-carboxycyclohexylcarbonyl)benzoic acid (M-2), p-(4-carboxycyclohexylhydroxymethyl)benzoic acid (M-3). Metabolite M-3 was detected only in dogs.
2) In rat plasma, the major metabolites were M-2, unchanged drug and M-1; while in dogs, unchanged drug, M-3 and M-1.
3) After oral and intravenous administration, M-2, unchanged drug and M-1 were mainly excreted to the urine in rats while in dogs, M-3, M-2 and unchanged drug were the main metabolites excreted to the urine.
4) M-2 was mainly excreted with bile in rats. In dogs, M-2 and M-1 were a major metabolites excreted to feces after intravenous administration.

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In the present study, we examined the distribution of TEI-5103 to gastric mucosa, as a target tissue, from the gastric lumen after oral administration of ¹⁴C-TEI-5103 to rats at its anti-ulcer dose (200 mg/kg).
When given orally, the radioactivity in gastric mucosa was much higher than that in plasma, unlike after intraduodenal administration. And the radioactivity in gastric mucosa was mostly present as unchanged drug, which was different from that in plasma. The concentration of unchanged drug in the gastric mucosa after oral administration was about 100 times higher than that after intraduodenal dosing. Additionally, radioactivity was observed in plasma after intragastric administration under pylorus ligation, indicating that TEI-5103 is at least absorbed from the gastric lumen.
In conclusion, we demonstrated TEI-5103 penatrated well to gastric mucosa as a target tissue directly from the gastric lumen after oral but not after systemic administration. These results suggest that TEI-5103 exerts its anti-ulcer effect by acting directly on the gastric mucosa when the drug is given orally.

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The absorption, distribution and excretion of ³H-S-3460 or ¹⁴C-S-3460 in various animal species were studied after topical application or subcutaneous administration.
1. The systemic availability after topical application of ³H-S-3460, as a 0.1 % ointment to normal skin of animals at 500 mg/kg was low, being only ca. 2 % of the applied dose in rats and rabbits and 0.2 % in dogs. The availability from stripped skins was ca. 40 % in both rats and rabbits.
2. The maximal plasma concentration of radioactivity and its appearance time after subcutaneous administration were: 110.7 ng equiv./ml and 2 hr in male rats, 62.8 ng equiv./ml and 1 hr in female rats, 174.1 ng equiv./ml and 4 hr in male rabbits and 89.8 ng equiv./ml and 30 min in male mice.
3. Radioactivity measurement after subcutaneous administration of ³H-S-3460 and whole-body autoradiographic observation after that of ¹⁴C-S-3460 revealed high levels of radioactivity in the liver, adrenal, kidney and pancreas in both male and female rats indicating that maximum levels would be reached in most tissues at 1 to 2 hr after administration.
4. Most of the radioactivity administered subcutaneously was excreted with the feces in male and female rats and mice, and excreted with the urine in rabbits. Biliary excretion of radioactivity as a percent of the dose was 82 % in male and 88 % in female rats. Approximately 30 % of the biliary radioactivity was reabsorbed from the intestinal tract in male rats.

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The absorption, distribution and excretion of S-3460 in male rats were studied following 7- or 28-day period of daily subcutaneous administration of ³H-S-3460 or ¹⁴C-S-3460 at 0.5 mg/kg.
1. The concentrations of radioactivity in plasma and blood 24 hr after daily administration rose with increasing of dosing times, and its concentration after the 28 th dose was 4.3 and 17 times higher than that after a single dose, respectively. Thus, it seems that the accumulation in plasma is low while that in blood is significantly high. Tissue concentration of radioactivity also rose and reached plateau levels by the 28 th dose in most tissues except for the blood, kidney and spleen.
2. The concentrations of radioactivity in the plasma, blood and most tissues after repeated administration of ³H-S-3460 were slightly higher than those after a single dose, but the disappearances were significantly slow. In some tissues, the levels after ³H-S-3460 administration differed from those after ¹⁴C-S-3460 administration. This may have been due to detachment of ³H from the 1, 2 position of ³H-S-3460. Tissue levels of radioactivity in female rats were lower than those in male rats and transfer of radioactivity with blood cell was also low.
3. Excretion of radioactivity into the urine and feces was almost constant during repeated administration and that after the 7 th or 28 th dose was similar to that after a single dose. Most of the radioactivity was excreted via the feces in both male and female rats.

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Transfer of ³H-S-3460 or ¹⁴C-S- 3460 into the fetus and milk were studied following subcutaneous administration to pregnant or lactating rats at dose of 0.5 mg/kg.
1. On day 19 of gestation, transfer of radioactivity into the fetus, determined by radioactivity measurement and whole-body autoradiography, was found to be significantly high in case of the liver, lung and intestinal contents. On the other hand, no radioactivity was detected on day 13 of gestation by whole-body autoradiography.
2. Transfer of radioactivity into milk was observed. Levels 2 to 6 times higher than those in maternal plasma ware found at all time periods of determination.

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The metabolism of ¹⁴C-S-3460 in rats, rabbits and mice was studied after subcutaneous administration at dose of 0.5 mg/kg. Plasma protein binding was also determined.
1. Plasma metabolites. The main metabolite was 21-hydroxy compound ((2)) and unchanged S-3460 was not detected in any of studied species. Other metabolites detected were 17, 21-dihydroxy compound ((4)) and 6, 7-dihydro and 17, 21-dihydroxy compound ((9)) in male and female rats, and other not identified metabolites. Almost the same amounts of (4) and (9) as well as (2) and unknovn compounds were presented in rabbits. Neither (4) nor (9) was detected in mice.
2. Urinary metabolites. In male and female rats, (4), (2), (9) and unknown metabolites each accounted for less than 1 % of the dose, but unchanged S-3460 was not detected. Almost equal amounts of (4), less of (2) and much more of (9) than that after a single dose were detected after repeated doses to male rats. In rabbits, the main metabolite (2) and many kinds of metabolites were detected but not the unchanged drug.
3. Biliary metabolites. Unknown metabolite B_f1 (13 % of the dose), conjugate of (2) (12 %), unknown metabolite Ba₁₄ (8 %) and Ba₂₂ (5 %) and many minor metabolites were detected in male rats. The main metabolite in female rats was the conjugate of (2), the amount of which was 2.5 times greater than that in male rats.
4. Plasma protein binding. Binding of ¹⁴C-S-3460 to rat and rabbit plasma in vitro was the same, 87 %, and to human plasma was about 97 %. Those in vivo were 85 to 88 % from 1 to 8 hr after dosing in male rats and rabbits.

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High-performance liquid chromatographic methods with fluorescence detection have been developed for monitoring the drugs such as leupeptin, antipain, bestatin, p-hydroxybestatin, forphenicinol and forphenicine which are protease inhibitors and also the possible therapeutic drugs for muscular destrophy. In the methods, these drugs are converted to fluorescent derivatives by suitable chemical reactions. The produced derivatives are then separated by high-performance liquid chromatography and determined by fluorometry. In the case for forphenicinol, the drug is not required for the fluorescence derivatization since the compound exhibits the native fluorescence. The proposed methods are simple and sensitive enough to permit the quantification of the drugs in biological samples from human and mouse dosed with the drugs. Thus, the methods are available not only for pharmacokinetic study but also for therapeutic examination of whether the drugs can enter the target organs at concentrations high enough to reveal their activities.

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Gastrointestinal absorption rate of benzodiazepines are relatively fast despite their water-insoluble characteristics in vitro. One of the reasons is their reversible reaction in acidic media simulated to stomach contents at 37 °C to produce the open-ring derivatives of the corresponding benzodiazepines, which are soluble in acidic environment because of the primary amine substituents formed. 450191-S, one of the open-ring compounds of benzodiazepines, is being developed as a water-soluble prodrug of benzodiazepine. Larger AUC of the active metabolite was reported after oral administration of 450191-S than corresponding benzodiazepine because of the avoidance of the hapatic first-pass extraction.

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