The absorption, distribution, metabolism and excretion of ¹⁴C-neticonazole (¹⁴C-SS717) were studied in rats after a single subcutaneous administration of 25mg/kg.
1. Blood levels of the radioactivity reached the maximum of 2.Olμg equiv. of SS717/ml (male) or 1.59μg equiv. of SS717/ml (female) at 4hr after dosing, and then declined slowly during 4 ?? 24hr with half-lives of 21 and 15hr in male and female rats, respectively. The elimination half-lives at the terminal phase (48 ?? 168hr) were 64hr (male) and 58hr (female).
2. Within 120hr after dosing in male rats, 65.4 and 29.5% of the dose were excreted in the urine and feces, respectively. No sex difference was observed in the excretion of radioactivity.
3. Biliary excretion of the radioactivity within 48hr after dosing was 51.9 and 46.7% in male and female rats. respectively. In male rats, 46. 7 and 2.0% of the dose were excreted in the urine and feces, respectively, while the excretion of radioactivity in female rats was 49. 6% of the dose in the urine and 2.7% of the dose in the feces. Also, the partial reabsorption of biliary excreta occurred from the intestinal tract.
4. Maximum levels of the radioactivity in most of tissues were reached at 4hr after dosing in male rats, and a high level of the radioactivity was observed in the adrenal gland, liver, kidney, aorta, fat and harderian gland. The distribution of radioactivity in the stomach was also visualized by the whole body autoradiography.
5. The extent of in vitro binding of ¹⁴C-SS717 to plasma proteins was 98.7 ?? 99.0% in rats, and 99.2-99.7% in human. The percent of in vivo binding of ¹⁴C-SS717 and/or its radioactive metabolites to the rat plasma proteins were 62.0-79.3% within 24hr after dosing.
6. In the plasma samples drawn from male rats at lhr after dosing, the percent of radioactivity of the unchanged drug was 20.5% and that of U-1 ?? U-3, U-5, U-6 and M3 metabolites were 1.9 ?? 7.8%. Subsequently, the unchanged drug declined gradually, but the most of metabolites increased until 4hr after dosing and thereafter declined.
In the urine excreted within 24hr after dosing, the percent of radioactivity of U-2 and U-6 metabolites were 17.1 and 14.1%, respectively, and that of U-1, U-3 ?? U-5 and five unknown metabolites were 0.5 ?? 9.7%. In the bile sample excreted within 24hr after dosing, the percent of radioactivity in U-2, U-5, U-6 and six unknown metabolites were 0. 2-2.2%. Meanwhile, in the enzymatically hydrolyzed samples, that of U-5, U-3, U-2, U-6 and 12 unknown metabolites were 0.59.5%, however, the most of those were observed for the first time.

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Transfer of ¹⁴C-neticonazole (¹⁴C-SS717) into the fetus and milk were studied in pregnant or lactating rats after subcutaneous administration, while the absorption, distribution, meta-bolism and excretion of ¹⁴C-SS717 were studied in male rats after repeated administration.
1. On day 13 and 18 of gestation, the radioactivity in the fetus was lower than that in the maternal blood as revealed by autoradigraphy. The distribution of radioactivity into the fetus was nearly uniform and any significant distribution to any tissue of fetus was not observed. The maximum level of radioactivity in the fetus was reached at 4hr after dosing and was lower than the maternal plasma level.
2. Milk levels of the radioactivity in lactating rats were 1.5 ?? 1.7 times higher than that found in the plasma until 8hr after dosing. However, the milk level of radioactivity at 24hr after dosing was same as plasma level, and was not detected at 48hr after dosing.
3. During the multiple dosing, the blood radioactivity level at 24hr after each dosing in-creased constantly with number of dosing and after the 21st dosing it was 3.8 times higher than that after the first dosing.
4. The cumulative excretion of radioactivity within 120hr after the 21st dosing accounted for 64.0 and 32.6% of administered dose in the urine and feces, respectively.
5. In the most of tissues examined, the concentrations of radioactivity reached the steady state within the 21st dosing. However, the accumulation of radioactivity was observed in aorta and skin. The disappearance of radioactivity from tissues after the 21st dosing was relatively slow.
6. In the plasma after the 21st dosing, the unchanged drug and U-2 metabolite, while in the urine U-2, U-5 and U-6 metabolites were detected as a major components.

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The absorption, distribution and excretion of ¹⁴C-neticonazole(¹⁴C-SS717), a new imidazole antimycotic, were studied in male rats and guinea pigs after dermal application of the drug as cream or solution formulations.
1. After dermal application (25mg SS717/2.5g cream/kg) of ¹⁴C-SS717 cream formulation in rats, the blood concentration of radioactivity reached the maximum level (30.0ng equiv. of SS717/ml) at 24hr, and the elimination half-life at the terminal phase was 97hr. The cumulative urinary and fecal excretions of radioactivity were 3.8 and 1.8% of applied dose during 120hr in rats after dermal application of ¹⁴C-SS717 cream formulation.
2. After dermal application (25mg SS717/2.5ml solution/kg) of ¹⁴C-SS717 solution formulation in rats, the blood level of radioactivity reached the maximum level (55.8 ?? 65.0ng equiv. of SS717/ml) at 8 ?? 32hr, and the elimination half-life at the terminal phase was 71hr. The cumulative urinary and fecal excretions of radioactivity were 3.6 and 1.7% of the dose during 120hr in rats after dermal application of ¹⁴C-SS717 solution formulation.
3. Microautoradiograms of dorsal skin after application of ¹⁴C-SS717 cream or solution(10 mg SS717/lg cream or 1ml solution/body) in guinea pigs suggested that ¹⁴C-SS717 distributed mainly into the stratum corneum following absorption via the transepidermal route, or partial absorption through the transfollicular route.4. Whole body antoradiograms demonstrated a high levels of radioactivity in the skin, at the application site and, in the intestinal content, bile, gastric content, in the urine presented in urinary bladder, liver, kidney and lung. No difference between these two preparations was observed in the distribution pattern of radiactivity.

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A total dose of 120 mg metoprolol tartrate was given to 12 healthy male volunteers as a slow-release metoprolol 120 mg tablet or conventional metoprolol 40 mg tablets t.i.d.. The two formulations were administered according to a cross-over design. Slow-release 120 mg tablet was administered after breakfast while the conventional 40 mg tablets were administered after breakfast, lunch and dinner.
The mean peak concentration (C_max) values (±SE) of the slow-release 120 mg tablets and conventional 40 mg tablets were 135.5±23. 2ng/ml and 105.8 ±15. 5ng/ml, respectively. The mean area under the concentration time curve(AUC_0-24) values (±SE) of the slow-release 120mg tablets and conventional 40 mg tablets were 1251.8±270.1 and 1141.3±224.3ng·hr/ml, respectively. AUC_0-24 values of individual volunteers in the slow-release 120 mg u, i, d conventional 40 mg tablets t. i. d. group correlated very well with each other(r=0.960, P<0.01).
Therefore, the bioavailability of slow-release 120 tablet u.i.d. was equivalent to that of conventional 40 mg tablets t.i.d..

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Slow-release metoprolol tartrate 120 mg tablets were given orally to 14 healthy male volunteers in the morning when fasting and after breakfast according to a cross-over design, and the influence of food intake on the bioavailability of the slow-release 120 mg tablet was examined.
Serum samples were collected from healthy volunteers receiving slow-release 120 mg tablets in the morning when fasting, and the binding of metoprolol to serum protein in vivo was determined using ultrafiltration method.
The mean peak concentration (C_max) values (±SE) were 86.6±11.1ng/ml in the preprandial state, and 119.6±17.1ng/ml in the postprandial state, and the mean area under the concentration time curve (AUC_0-24) values (±SE) were 896.7±150.3ng•hr/ml and 1140.0±196.0ng•hr/ml, respectively. The mean C_max values and AUC_0-24 values in the postprandial state were significantly higher than the corresponding values in the preprandial state, but the mean time to peak concentration (T_max) values in the preprandial and postprandial state were not significant.
The mean percentage of serum protein binding values at 4, 9 and 12 hr when fasting were 19.8%, 21.0% and 32.2%, respectively.

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Slow-release metoprolol tartrate 120mg tablets were given orally to 6healthy male volunteers u.i.d. on each of 10 days. Plasma metoprolol concentrations were measured according to the protocol during each of 10 days.
The mean peak plasma concentration(C_max) values and the mean area under the concentration time curve (AUC_0-24) values on day 5, day 7 and day 10 were not statistically significant. The mean plasma levels at 24h on each of 10 days were not significant, and particularly the plasma levels at 48h on day 10 were below detection limit (<2 ng/ml) except one subject. Therefore, the accumulation of metoprolol after administration of the slow-release 120 mg tablet u.i.d. was not observed.

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Pharmacokinetics of methylprednisolone aceponate(MPA) was investigated after subcutaneous administration of [6-¹⁴C-methyl]-MPA to rats.
1. The radioactivity in the plasma reached Cmax at 0.3 h, and disappeared from the plasma with a half-life of 1 h. AUC and plasma levels in male rats were 2-fold higher than those in females.
2. Binding to plasma protein in vitro and in vivo accounted for 94%.
3. The radioactivity distributed rapidly and widely to tissues. Most tissues, especially liver and kidney, showed higher conc. than in the blood. The maximum was found within 1 h, and disappeared almost completely from tissues by 120 h. The disappearance from the blood of male rats was slow (T_1/2 in the last phase:> 150 h). Though the conc. in tissues showed higher values in male than female, the C_tissues/C_blood were similar in both sex.
4. During the repeated subcutaneous administration, the conc. in tissues of female rats showed no accumulation. In male rats, the conc. in tissues, especially in the blood, raised by the repeated administration. The increase of the conc in tissues was caused by the higher blood level, and the accumulation in tissues was not found. Excretion to urine and feces was complete.
5. The conc. in fetus was lower than that in maternal plasma, and showed practically no transfer to milk.
6. The excretion of the radioactivity into urine and feces within 120 h were 2 ?? 6% and 90 ?? 96% of the dose, respectively. The biliary excretion was 80% (-24 h). About 15% of the radioactivity in the bile underwent enterohepatic recirculation.
7. MPA was not found in the plasma already at 15 min, and the main metabolites in the plasma were methylprednisolone-17-propionate (MP-17P, female, male), methylprednisolone (female) and highly polar unidentified metabolites (male). Most of radioactivity excreted to the bile consisted of a major metabolite identified as sulfate conjugate of MP-17P (female;> 90%, male;> 20%). Several unidentified metabolites were found in male rats.

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The absorption, distribution, permeability, metabolism in skin and excretion were investigated after topical application of [¹⁴C-methyl] labelled and unlabelled MPA (100mg ointment/0.5mg MPA/kg) to rats.
1. Plasma level of radioactivity after topical application through the intact skin was very low (<0.5ng eq./ml), while using the stripped skin, removing stratum corneum with olive tapes, plasma levels greatly increased (ca. 10 times) as compared with those observed in intact skin experiment. The absorption rate of MPA through stripped skin was faster than that of ³H-betamethasone(BT) in the early phase of the application, but there was no difference in AUC_0-24h of MPA and BT.
2. The highest level of radioactivity was found in the upper site of the stratum corneum 4h after application to intact skin. At 24h after application, main fraction of the radioactivity was found in deeper layer of the stratum corneum. Very low level was found in corium at both time points. The distribution of MPA to stratum corneum was faster than that of BT.
3. At 4h after application to the stripped skin, amount of MPA remaining on the skin surface was lower (37%) when compared with other drugs, so there was a predominant permeability of MPA to the corium.
4. No metabolites could be detected in the stratum corneum. The main metabolite in the corium was methylprednisolone 17-propionate (MP-17P) (30%), and MPA was about 60%.
5. Radioactivity was excreted in urine (7%) and feces (60%) within 96h after the application, and the residual radioactivity (37%) was recovered from the skin surface.

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An analgesic efficacy of IMF and the metabolism were examined after oral administration of ¹⁴C-labelled indometacin farnesil (IMF) in the dog arthritis model, and were compared with those of indomethacin (IND).
1. IMF have shown the analgesic effect in a dose-dependent manner and an effective dose of IMF was greater than 3mg/kg, whereas IND was at 0.3mg/kg. Based on pharmacological study, the metabolic studies were carried out with both ¹⁴C-labelled IMF (¹⁴C-IMF) and IND (¹⁴C-IND) at a dose of 10mg/kg and 3mg/kg, respectively.
2. Cmax and AUC (0-6hr) values in the blood were not different between ¹⁴C-IMF and ¹⁴C-IND dosing, however the Tmax was greater in the case of ¹⁴C-IMF than that after ¹⁴C-IND dosing.
3. Following ¹⁴C-IMF dosing, concentrations of radioactivity in the inflamed site (synovial tissue and synovial fluid) were approx. 2 times greater than those in normal site. Radioactivity in inflamed site was present mainly as unchanged IMF, however, IND released from IMF was also present of several times lower levels than those of unchanged IMF. The levels of IMF and IND, as well as total radioactivity in inflamed site were higher at 6hr than those at 3hr. In the dosing of ¹⁴C-IND, both concentrations of radioactivity and IND in inflamed site were comparable with those in the normal sites, which levels were equal or lower when compared with those of ¹⁴C-IMF dosing.
4. Hydrolytic enzyme activity toward IMF was highest in the liver, followed by kidney. The enzyme activity was not observed in plasma, but was present in synovial fluid obtained from inflamed site.
5. Based on these results, it was demonstrated that IMF has an analgesic efficacy in dogs with carrageenin-induced arthritis. And it was suggested that IMF has a characteristic property of being transported as unchanged form into the inflamed site and then hydrolyzed to IND in the site, which might be comparable with that in human.

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To elucidate the efficacy of TA-870 as a dopamine prodrug, plasma concentrations of metabolites after oral administration of TA-870 or dopamine hydrochoride (DA) to dogs were measured by high performance liquid chromatography. The in vitro metabolism of TA-870 in various animals was also studied. Maximum levels of free DA (active from) in dog plasma after dosing of TA-870 (33.5mg, 71μmol/kg) and DA (13.5mg, 71μmol/kg) were 252ng/ml and 29ng/ml, respectively, the maximum level after dosing of TA-870 being about 9 times higher than that of DA. Ethoxycarbonyl and acetylme thionyl groups in TA-870 structure, designed to protect the catechol and amino groups of DA, successfully suppressed the first pass metabolism of oral DA.
Hydrolysis rate of TA-870 by plasma esterase of different animal species was in the order as follows, rat> guinea pig≈rabbit > human > dog. TA-870 was not converted to DA in the presence of dog plasma, however the conver sion took place in the presence of whole blood of the dog. Conversion rate of TA-870 to DA in different rat tissues was in the order as follows, liver> small intestinal well> blood.

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The absorption, distribution, metabolism and excretion of Oxiracetam (CT-848) were studied in rats after single administration of ¹⁴C-CT-848.
1. After oral administration of 10mg/kg of ¹⁴C-CT-848 to male rats, the plasma concentration of radioactivity reached Cmax 2hr after dosing and decreased rapidly with half-lives of 1.2hr (4 ?? 8 hr) and 3.6hr (8 ?? 12hr).
2. The plasma pharmacokinetics was not directly dose-proportional after oral administration with 10mg/kg, 50mg/kg and 250mg/kg. They were also slightly altered by food (T_max : 1 hr, T_1/2 : 2.5hr, 4.4hr) but did not differ between the sexes. μ3. Radioactivity was distributed in all tissues, especially in the gastroin testinal tract, bladder and kidney but only low levels were found in the cen tral nervous system.
4. Radioactivity was rapidly excreted predominantly via the kidney and elimination was almost completed within 24hr after dosing.
5. After oral administration to fasted male rats, only unchanged compound was observed in the plasma. In urine and feces up to 24hr the radioac tivity almost corresponded with unchanged compound and about 1 % of the radioactivity were unknown metabolites.

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The absorption, distribution, metabolism and excretion of Oxiracetam (CT-848) were studied in male rats during and after the consecutive oral administration of 10mg/kg of ¹⁴C-CT-848 for 14 days.
1. The plasma concentrations of radioactivity at 1hr and 6hr after each dose were not affected by repeated administration. After the 14th doses, radioactivity in plasma reached Cmax at 1hr and decreased with a half-life of 1.6hr (2 ?? 8 hr).
2. The concentrations of radioactivity in tissues at 6hr were not significantly different between after 7th and 14th doses and 1st dose. The elimination of radioactivity from tissues was rapid after the 14th dose. Accumulation of radioactivity in tissues was not observed.
3. The extents of excretion in urine and feces during consecutive oral do sing were 27.2 ?? 31.3%, and 52.7?? 72.1%, respectively. The elimination of radioactivity from the body was completed by 48hr after the final administration.
4. After repeated oral administration to non-fasting male rats, only unchanged compound was observed in plasma at 1hr and 6hr. In urine and feces up to 24hr after 1st and 14th doses only about 1 % of the recovered radioactivity was corresponded to unknown metabolites and the remainder was unchanged compound.

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The distribution of radioactivity of ¹⁴C-labelled Oxiracetam (¹⁴C-CT-848) in the fetus and its transfer into milk were studied after single oral administration at a dose of 10mg/kg to pregnant or lactating rats.
1. On day 12 of gestation, radioactivity was not observed in the fetus 1hr after the dosing. The concentrations of radioactivity in uterus, placenta and fetal membrane were the same as that found in maternal blood.
2. On day 18 of gestation, radioactivity in fetus and fetal membranes was higher than that found on day 12 of gestation. Radioactivity in the plasma and tissues of dams reached C_max at 1hr but the C_max in fetal tissues and amniotic fluid was observed at 6hr. Fortyeight hours after dosing only low levels of radioactivity were observed in amniotic fluid and fetus at 9 ?? 4% of maximum levels.
3. After oral administration of ¹⁴C-CT-848 to lactating rats, radioactivity in milk reached C_max at 4hr and was not observed at 24hr after dosing.

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