The absorption, distribution and excretion of suplatast tosilate, (±)-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]dimethylsulfonium p-toluenesulfonate (IPD-1151T) were studied in rats after a single or repeated administration of ¹⁴C-labeled-IPD-1151T.
1. After oral administration, the blood radioactivity reached the C_max at 8hr and then decreased with half-life of 12day, and the blood-to-plasma level ratio became high. It seems that elmination of radioactivity from blood cell was very slow. It is suggested that absorption of IPD-1151T was affected by food as manifested by the decrease of blood radioactivity in fasting rats.
2. Approximately 87% and 11% of radioactivity was excreted during 72hr after intravenous administration in urine and feces, respectively and corresponding values for oral administration were approximately 26% and 73% in urine and feces.
3. About 9 % and 17% of radioactivity was excreted in bile after intravenous and oral administration, respectively. When the bile was administered, more than 90% of radioactivity present in the bile was reabsorbed. This result suggested the presence of the entero-hepatic circulation.
4. A high radioactivity was found in the intestine, urinary bladder, mesenteric lymph node, pancreas, kidney, seminal vesicle and liver after oral administration, and it disappea red slowly from any tissue.
5. After oral administration, the blood and tissue radioactivities and the excretion of radioactivities in urine and feces did not essentially differ between male and female rats.
6. The blood radioactivity gradually increased during repeated oral administration and on day 27, the blood radioactivity reached a plateau. While there was not any definite accumulation in any particular organ or tissue after repeated administration.
7. After oral administration to pregnant rats, the radioactivity in fetuses were lower than that in maternal organ (liver, kidney, ovary, uterus, amnion and placenta).
8. When administered to lactating rats, the radioactivity was transfered into the milk up to the same level as maternal plasma, and disappeared rapidly from the milk as that in maternal plasma.

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We have identified the metabolites of suplatast tosilate, (±)-{2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl}dimethylsulfonium p-toluenesulfonate(IPD-1151T)present in the plasma, urine and bile after oral administration of IPD-1151T and have studied the biotransformation of IPD-1151 T after oral administration of ¹⁴C-labeled IPD-1151T (¹⁴C-IPD-1151T) in rats.
1. Following metabolites were identified in the rat plasma, urine and bile ; (±)-4-(3-ethoxy-2-hydroxypropoxy)acrylanilide (M-1), (±)-4-(3-ethoxy-2-hydroxypropoxy)acetoanilide(M-2), (±)-4-(3-ethoxy-2-hydroxypropoxy)propionanilide glutathione conjugate (M-1-GSH), (±)-4-(3-ethoxy-2-hydroxypropoxy)propionanilide cysteinylglycine conjugate (M-1-Cys•Gly), (±)-4-(3-ethoxy-2-hydroxypropoxy)propionanilide cystein conjugate (M-1-Cys), (±)-4-(3-ethoxy-2-hydroxypropoxy)propionanilide mercapturic acid conjugate (M-1-Ac•Cys), (±)-4-(3-ethoxy-2-hydroxypropoxy)propionanilide mercapturic acid S-oxide conjugate [M-1-Ac•Cys(S→0)], (±)-4-(3-ethoxy-2-hydroxypropoxy)-[3(methylsulfinyl)propion]anilide [M-1-CH₃SH(S→0)]
2. After oral administration of ¹⁴C-IPD-1151T, the plasma radioactivity mainly consisted of IPD-1151T base at 1hr and its radioactivity disappeared rapidly. C_max of M-1 was observed at 2hr after administration and disappeared slowly. Also radioactivity derived from some other metabolites was detected in plasma. Radioactivity relating to an unidentified metabolites increased in time-dependent manner.
3. Approximately 24% and 43% of radioactivity were excreted during 24hr after oral administration in urine and in feces, respectively. And a relatively high radioactivities correponding to metabolites (M-1-Ac•Cys and M-1-CH₃SH(S→O)) were observed. The ratio of identified metabolites to the total radioactivity excreted in urine was about 29%. Otherwise, the most radioactivity in feces was consisted in IPD-1151T base.
4. After oral administration of ¹⁴C-IPD-1151T to bile-duct cannulated rats, the radioactivity was excreted about 24% and 14% of the dose in urine and in bile, respectively. The major radioactivities consisted in M-1-GSH, M-1-Cys•Gly and M-1-Cys. Urinary excretion of M-1-CH₃SH(S→O) in bileduct cannulated rats was about 13% of that in intact rats. This result suggested that microflora contributed to the biotransformation to thiol compound. The ratio of identified metabolites to the total radioactivity excreted in bile was about 25% and that in urine was about 11%.
5. Orally dosed IPD-1151T was metabolized to M-1. M-1 was metabolized to M-1-Cys, M-1-AcCys and M-1-CH₃SH(S→O). These metabolites underwent through the entero-hepatic circulation and were excreted in the urine.

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The pharmacokinetics of suplatast tosilate, (±)-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]dimethylsulfonium p-toluenesulfonate(IPD-1151T) after oral and intravenous administration was studied in the mice, rats, guinea pigs, dogs and monkeys. In order to clarify the metabolic pathways in detail, we examined (±)-4-[3-ethoxy-2-hydroxypropoxylacrylanilide (M-1) disposition after intravenous administration and the stability of IPD-1151T in vitro.
1. The maximum plasma levels of unchanged IPD-1151T base (IPD-1151T base) in the dog was the highest among examined animals and was about 10 times higher than that in rats. Area under the concentration time curve(AUC)of IPD-1151T base in the dog was the hightst, too. In the plasma, metabolites, (±)-4-(3-ethoxy-2-hydroxypropoxy)propionanilide cysteine conjugate (M-1-Cys), (±)-4-(3-ethoxy-2-hydroxypropoxy)propionanilide mercapturic acid conjugate (M-1-Ac•Cys), (±)-4-(3ethoxy-2-hydroxypropoxy)-[3-(methylsulfinyl)propion]anilide (M-1-CH₃SH(S→O) derived from glutathione conjugate were observed in all examined animals. Contrary to, after intravenous dosing, IPD-1151T base was mainly observed while metabolites accounted only for a small quantity of M-1 in plasma in mice, rats and dogs. This results suggested that orally dosed IPD-1151T base was subjected to the first pass effects.
2. When IPD-1151T was orally administered, IPD-1151T base and metabolites, M-1-Cys, M-1-Ac•Cys, M-1-CH₃SH(S→O) derived from glutathione conjugate were excreted in urine. Sum of urinary excreted IPD-1151T base and its metabolite were different among all species.
3. When IPD-1151T was orally administered, IPD-1151T base was mainly excreted in all examined animals.
4. When IPD-1151T was orally or intravenously administered to the bile duct cannulated rats, the major biliary product was M-1-Cys and excreted IPD-1151T base accounted for a small quantity.
5. We have studied urinary metabolites after intravenous or intraportal infusion of IPD-1151T in the rat and the stability of IPD-1151T base in the small intestine and small intestinal juice in vitro. Based on these results, postulated metabolic pathways are as followe : orally administered IPD-1151 T was partially metabolized to M-1 in small intestine, and both IPD-1151T base and M-1 were absorbed. IPD-1151T base was excreted in the urine as an unchanged product, while M-1 was metabolized to glutathione conjugate and their further metabolites and excreted in urine.
6. Serum protein binding of IPD-1151T base was very low. Serum protein binding of M-1 was higher than that of IPD-1151T base and its species-related differences in protein binding were observed.

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The absorption, distribution, metabolism and excretion of radioactivity were investigated after a single oral administration of ¹⁴C-felodioine 1 mg/kg to does of both sexes.
1. Radioactivity concentration in the plasma of male dogs reached a C_max of 2, 228ng eq./ml at 2hr and then declined with half-lives of 4.8hr up to 8hr, 16hr from 12hr to 48hr and 123hr from 72hr to 168hr after administration. Radioactivity concentrations in the blood were 51 ?? 62% of those in the plasma. The AUC_0-∞ was 41.3μg•eq. hr•ml^-1. Profiles of radioactivity concentrations in the blood and plasma of female dogs were similar to those in male dogs.
2. In male dogs, 54.9 and 41.4% of the dose was excreted in the urine and feces within 168hr, respectively. In female dogs, 55.8 and 38.9% of the dose was excreted in the urine and feces within 168hr, respectively. The excretion of radioactivity was not sex dependent.
3. In the plasma, the parent compound was a minor substance and M-III and M-IV were mainly found. In the urine, M-III, M-IV and M-V were the major metabolites, while in the feces, M-III, M-IV, M-VI (lactone) and M-VII (lactone) were mainly found. Hardly any sex difference was present in the relative amounts of metabolites in the plasma, urine and feces. The major metabolites UM1 and UM2 found in the plasma of rats were not present in the plasma of dogs.

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We investigated the absorption, distribution and excretion of ³H-TJN-101 following single oral administration of the drug in rats.
1. The concentration of radioactivity in blood increased rapidly after oral administration of 4 mg/kg of ³H-TJN-101 in male rats and reached C_max of 816ng/ml (TJN-101 base) at 0.75hr. Thereafter, the radioactivity decreased, with a half-life of 1. 1hr up to 4 hr and with a half-life of 7.6hr from 6 to 24hr after dosing. The concentration dropped below the detection limit at 48hr. The area under the concentration-time curve (AUC_0-24h) was 3.12μg•hr/ml. Following oral administration of 0.8mg/kg of ³H-TJN-101 in male rats, both C_max and AUC_0-24hr were 12% of the values of the 4 mg/kg group. C_max and AUC_0-24h, following oral administration of 20mg/kg of ³H-TJN-101 were 5.4 and 9.2 times of the values of the 4 mg/ kg group, respectively.
2. In female rats, at 0.75hr after oral administration of 4mg/kg of ³H-TJN-101, C_max was 682ng/ml, and it decreased, with a half-life of 2.9hr up to 8hr after dosing. C_max and AUC_0-24h, were 84% and 1.3 times of those in the male rats, respectively.
3. Tissue radioactivity after oral administration of 4mg/kg of ³H-TJN-101 reached the maximum level within 0.25 to 0.75hr, being higher in the liver, and lower in the central nervous system, testis, and eyeball.
4. Within 168hr after oral administration of 4mg/kg of ³H-TJN-101, radioactivity in the urine and feces in male rats was 13.6% and 83.1% of administered dose, respectively, and that in female rats was 20.9% and 73.9% of the dose, respectively.
5. Within 48hr after dosing, 91.1% of the total radioactivity was detected in the bile and 4.5% in the urine, as determined simultaneously.
6. Within 48hr after intraduodenal administration of radioactivie bile obtained from other rats which had been administered ³H-TJN-101 orally, 52.0% of injected radioactivity was excreted in the bile and 4.0% in the urine.

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The transfer of ³H-TJN-101 to the fetus and milk was studied following single oral administration of ³H-TJN-101 (4 mg/kg) to pregnant or lactating rats.
1. On days 12 and 18 of gestation, the radioactivity in the fetus at 0.75hr after oral dosing was 36% and 50% of the maternal plasma level, respectively. The radioactivity at 24hr after dosing was lower by 2 % and 5 % than that observed at 0.75 hr, respectively.
2. Transfer of radioactivity to milk was observed following oral administration of ³HTJN-101 to lactating rats on day 11 after delivery. The radioactivity in the milk reached the maximum at 0.75hr, which was the first measurement period after dosing, and decreased with a half-life of 1.2hr up to 4hr, and with a half-life of 12hr from 8 to 48hr after dosing. The radioactivity level in the milk was 2.9 times higher than that in plasma as measured simultaneously 0.75hr after the oral dosing ; however, 8hr after dosing, the levels in milk were almost the same as those in plasma.
3. The tissue distribution study on days 12 and 18 gestation, revealed that the total radioactivity levels in the fetus were lower by approximately 50% than those in maternal plasma.

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The absorption, distribution, and excretion of ³H-TJN-101 in male rats were studied following 21-day period of daily oral administration (4 mg/kg/day).
1. The radioactivity level in the blood at 1 and 24hr after oral administration rose as the number of doses increased, and the concentration at 1 and 24hr after the 21st dose was 1.6 and 3.9 times higher, respectively, than those after the first dose. The elimination half-life from 48hr after the 21st dose was 2.9 times longer than that after the first dose.
2. The concentrations of radioactivity in most tissues at 24hr after daily administration rose as the number of doses increased, but the elimination was slower in comparison with that after single dose.
3. Excretion of radioactivity in the urine and feces was almost constant after the 4th dose. One hundred and sixty-eight hr after the 21st dose, 12.9% and 80.6% of the radioactivity administered was excreted in the urine and feces, respectively.

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The Metabolism of TJN-101 was studied in rats after oral administration of ³H-TJN-101.
1. At 0.75hr after the oral administration of ³H-TJN-101 (4mg/kg) to fasted rats, 30.0%, 18.1%, and 8.5% of the radioactivity was present in the plasma as unchanged TJN101, Met. A III, and Met. A I, respectively. At 1hr after a single dose and at 1hr after the 21st daily oral administration to non-fasted rats, the ratio of unchanged TJN-101 to total radioactivity in the plasma was 18.1% and 19.6%, respectively.
2. In the liver, at 0.75hr after a single oral administration to fasted rats, 15.3%, 26.3 %, and 6.3% of the radioactivity was present as unchanged TJN-101, Met. A-III, and Met. F, respectively. At 1hr after the 21st administration, only Met. A-III was found in the liver, accounting for 16.0% of the total radioactivity.
3. In the bile collected for 24hr after a single oral administration to fasted rats, most of the metabolites were present in the conjugated form, Met. B, Met. F, and Met. D accounted for 41.3%, 9.4%, and 9.2% of the total radioactivity, respectively.
4. Urine, collected for 24hr after a single oral administration, was enzymaticaly hydrolyzed. The percentages of radioactivity corresponding to Met. B, Met. F, and Met. D were 29.6 %, 16.5%, and 9.0%, respectively. The other metabolites accounted for less than 6 % of the radioactivity. After hydrolysis of urine collected for 24hr from non-fasted rats after a single dose or after the 21st daily dose, Met. B was present, accounting for 32.4% and 39.9% of the total radioactivity, respectively. Almost no differences were found in the composition of the other metabolites in non-fasted rats compared with those in fasted rats.
5. Six metabolites were observed in feces collected for 24hr after a single oral administration to fasted rats, and these constituted less than 9 % of the total radioactivity. In feces collected for 24hr after the 21st daily administration to non-fasted rats, 18.0%, 11.2% and 10.9% of total radioactivity was present as Met. B, Met. F, and an unknown metabolite, M₁, respectively.

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Bioequivalence of defferent products of the same drug is very important where many generic drug products are on the market. Data of bioequivalence tests have been analyzed using pharmacokinetic model independent parameters. However, model dependent methods merit being considered as an analysis method to assess bioequivalence/bioavailability. We have studied the application of NONMEM to evaluation of bioequivalence/bioavailability, which is one of the methods used for analysis of population pharmacokinetics. In this paper, decision-making rules in bioequivalence assessment, an application method of NONMEM to the evaluation of bioequivalence and the relationship between a decision-making rule and the NONMEM method were shown. The results of comparison of the confidence intervals for the difference in bioavailability estimated by NONMEM and a model independent method were summarized, which indicated the usefulness of the NONMEM method for evaluation of bioequivalence using experimental and obsevational data. Merits and demerits of NONMEM for assessing bioequivalence/bioavailability were discussed.

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