The plasma levels, tissue distribution, metabolism and excretion of ¹²⁵I-KRN8601 after a single intravenous administration were investigated in male and female rats.
After an intravenous administration of ¹²⁵I-KRN8601 at a dose of 5μg/kg, plasma levels of total, trichloroacetic acid (TCA) precipitable and immunoreactive radioactivity decreased in biphasic manner. More than 90% of radioactivity in plasma was retained to be TCA precipitable and immunoreactive for one hour following the administration. There was no difference in the half-life, distribution volume and AUC between male and female rats. In the case of increasing of dose level, no differences in the half-life and distribution volume were observed, while AUC increased proportionally to administered dose level.
Ten minutes after intravenous administration, high levels of radioactivity were observed in the plasma, adrenals, blood, kidney, thyroid, liver and bone marrow. Radioactivities in most tissues were below the plasma level and decreased in parallel with that in any time interval. Low radioactivity levels were detected in the brain, eyes, skeletal muscle, thymus and adipose tissue. These results were in good agreement with those of whole body autoradiograms. Distribution profiles of radioactivity in female did not differ from those in male rats with the exception of genital organs. TCA precipitable radioactivities were shown at high level in the kidney, liver and spleen and in plasma as well, but a low level was detected in the stomach and small intestine.
Within 72 hours after intravenous administration, most of the administered radioacitvity was excreted in urine in the form of free iodine. Biliary excretion of rdioactivity was also observed, mostly as compounds of low molecular weight.

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The transfer of ¹²⁵I-KRN8601 to the fetus or into the milk after a single intravenous administration was investigated in pregnant rats on 19 days of gestation or in lactating rats.
At any time interval after intravenous administration, radioactivity level in the fetus was thirty times lower than that in maternal plasma. It suggests that KRN8601 administered to pregnant rat is not distributed to the fetus.
Radioactive substances of high molecular weights were found in the milk of lactating rats given ¹²⁵I-KRN8601 intravenously. However none of the radioactive substances were unchanged compounds. Most of the substances are considered to be endogenous high molecular weight compounds into which free iodine produced by degradation of ¹²⁵I-KRN8601 was incorporated.

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Plasma level, distribution and excretion of ¹²⁵I-KRN8601 after sixth cosecutive daily intravenous administrations were examined in male rats.
After sixth intravenous administration of ¹²⁵I-KRN8601 at the dose of 5μg/kg/day, the plasma levels of total and trichloroacetic acid precipitable radioactivity declined more slowly than those after a single administration, whereas no difference in the plasma level profile of immunoreactive radioactivity was seen when compared to that after a single administration.
Except the thyroid which showed the extremely high level of radioactivity, the concentration of radioactivity in each organ decreased with time after repeated administration, and no accumulation of ¹²⁵I-KRN8601 in any particular organs or tissues was observed.
Excretion of radioactivity in urine and feces was almost constant, i.e. over 70% and 4 ?? 6 % of each administered dose, respectively, during repeated administration. Finally, more than 90% or the administered radioactivity excreted in the urine and feces within 96 hours after the last dosing.
All the radioactivity excreted in urine appeared to be low molecular weight compounds.

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A specific radioimmunoassay method was developed for H-Met(O₂)-Glu-His-Phe-D-Lys-Phe-NH(CH₂)₈-NH₂(ebiratide)., an analogue of adrenocorticotropic hormone. The sensitivity was 30pg/ml. Recovery of ebiratide from plasma was almost 100%, and the intra and inter-assay coefficients of variation were less than 15%. Plasma levels and urinary excretion of ebiratide were determined in six healthy male volunteers after intravenous administration of ebiratide (150μg). Ebiratide was eliminated from the plasma in a biphasic pattern, with half-lives of 3.2min (first phase) and 3h (second phase), and 0. 76% of the dose was excreted in urine. These results indicate that this radioimmunoassay method is suitable for analyzing the pharmacokinetics of ebiratide.

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The absorption, distribution and excretion of 883-S(ceruletide diethylamine), a new agent against dyskinesia, were studied in rats using ¹⁴C-883-S. Radioactivity in the plasma decreased rapidly during 30min after i.v. administration (0.1mg/kg) followed by an increase up to 6hr. The radioactivity decreased slowly thereafter and still remained at 10 days after i.v. administration. The half-life time of the radioactivity in the plasma immediately after administration (0.1-1 mg/kg) was about 2min, but that of unchanged 883-S (0.01-1 mg/kg), analyzed by HPLC, radioimmunoassay and bioassay was about 1min. Radioactivity levels in the plasma immediately after administration were in order of i.v. >i.m.>s.c.>i.p.. In all cases, an increase of plasma radioactivity was observed from 30min after each administration.
Urinary, fecal and expiratory excretion over 10 days were 23%, 4 % and 42 % of the administered radioactivity, respectively. Twenty six percent of the administered radioactivity still remained in the carcass 10 days after administration. Biliary excretion during 24hr accounted for 21% of the administered radioactivity.
Tissue distribution of radioactivity was highest in the kidney and pancreas. The radioactivity levels of many tissues resembled that in the plasma except for the brain and testis. An extremely low but measurable concentration of 883-S was found in the brain by radioimmunoassay.

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The distribution of ¹⁴C-883-S (ceruletide diethylamine) in male rats, pregnant rats and male mice was studied using a whole body autoradiography technique. The highest radioactivity was seen in many tissues at 5min after i.v. administration of 5mg/kg. The highest level of radioactivity was found in the kidney followed by the liver, pancreas, salivary gland, thyroid, lung and blood in descending order. The radioactivity of the pancreas, bone marrow, thyroid, salivary gland, pituitary gland and mucosa of the gastrointestinal tract increased gradually for 4hr and decreased slowly thereafter.
In pregnant rat, fetal radioactivity was not detected immediately after administration but increased gradually thereafter, with the highest level being observed at 24hr after administration for fetuses of both 12 and 19 days gestation. Radioactivity was still observed in mather and fetus 8 days after administration in rat of 12 days gestaion.
The distribution pattern in male mice resembled that in rat, for example, the radioactivity of the pancreas, bone mallow, salivary gland, mucosa of gastrointestinal tract, spleen and skin increased gradually for 4hr.

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Metabolism of 883-S (ceruletide diethylamine) was studied in rats after intravenous administration of ¹⁴C-883-S (alpha carbon of glycine residue was labeled with ¹⁴C).
The plasma level of unchanged 883-S rapidly decreased after injection. The level of unchanged 883-S was less than 10% of the total radioactivity present in the plasma 5min after injection. A major metabolite, present in plasma in the early phase, was a neutral peptide longer than tripeptide. One hour after injection, the radioactivity appeared in the plasma protein fraction, probably due to an extensive hydrolysis of 883-S and subsequent incorporation of ¹⁴C-glycine moiety into the protein via biosynthetic pathway. In the urine, unchanged 883-S was not detected. The major urinary metabolite was ceruletide-(1-6) peptide, Pyr-Gln-Asp-Tyr (SO₃H)-Thr-Gly. The radioactive metabolites in the bile were separated into two fractions. The major fraction contained unchanged 883-S, and the minor one contained ceruletide-(1-6) peptide, the same metabolite found in the urine.

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The absorption, metabolism and excretion of ¹⁴C-KT1-32 were studied in dogs after a single oral, intravenous and repeated oral administrations of 1 mg/kg.
1. The radioactivity in the plasma reached a maximum level (3.46μg eq./ml) at 1.93hr after a single oral administration to male dogs.
2. The radioactivities in the plasma declined biexponentially with half-life times of 1.98hr and 39.6hr after a single intravenous administration to male dogs.
3. Within 96hr after a single oral administration, the excretions of radioactivity into urine and feces amounted to 74% and 25% of the administered dose, respectively.
4. In the study with repeated oral administration, the radioactivity in the blood reached the steady state within 24hr after the 3rd administration. The ratios of cumulative excretion into urine and feces were practically constant during the repeated administration. The ratios of the cumulative excreation were 59% in urine and 40% in feces, respectively.
5. The intact drug was found as the major component in plasma, urine and feces after a single oral or intravenous and repeated oral administrations.

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The binding to various proteins and the uptake by erythrocytes of ¹⁴C-KT1 -32 and its major metabolites (¹⁴C-M1, ¹⁴C-M2) were studied. The binding of ¹⁴C-KT1-32, ¹⁴C-M1 and ¹⁴C-M2 to total plasma, albumin, α₁-acid glycoprotein(AAG) and γ-globulins were determined in humans and various animals in vitro, ex vivo and in vivo. The uptakes by erythrocytes were determined in humans, rats and dogs in vitro or in vivo.
1. The binding of ¹⁴C-KT1-32, ¹⁴C-M1 and ¹⁴C-M2 to plasma and albumin were greater than 97%. AAG and γ-globulins bindings of ¹⁴C-KT1-32, ¹⁴C-M1 and ¹⁴C-M2 were less than 15%.
2. Protein binding of ¹⁴C-KT1-32 to rat, dog and human plasma was characterized as reversible.
3. Protein binding of ¹⁴C-KT1-32 to human plasma was not affected by the additions of cimetidine, ranitidine, famotidine and bromazepam. Protein binding of ³H-cimetidine, ranitidine, famotidine and bromazepam to human plasma was also not affected by the addition of KT1-32.
4. The uptakes of ¹⁴C-KT1-32 by erythrocytes of humans and various animals were less than 41% in vivo or in vitro.

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The absorption, distribution and excretion of [3, 4-di(4-methoxyphenyl)-5-isoxazolyl] acetic acid (mofezolac) were studied in rats after a single or repeated oral administration of ¹⁴C-labeled-mofezolac.
1. Concentration of radioactivity in the blood increased rapidly after oral administration, reaching C_max within 15min, and decreased to 1.4% of the maximum level 12hr after administration.
2. Approximately 55% and 39% of radioactivity were excreted during 72hr after administration in urine and feces, respectively.
3. About 62% of radioactivity was excreted in bile. When the bile was administered, about 52% of radioactivity present in the bile was re-absorbed. This result suggested the presence of the entero-hepatic circulation.
4. Tissue radioactivity was higher in the stomach, liver and kidney, while the radioactivity in other tissues was lower than that in plasma. Radioactivity disappeared rapidly from any tissue.
5. When female rats were administered ¹⁴C-mofezolac on day 11 or 18 of pregnancy, or slight radioactivity usually lower than in maternal plasma was observed in the fetus. Radioactivity in fetus as well as in maternal tissues disappeared rapidly. Radioactivity in the fetus was not detected at 24hr after administration.6. Concentration of radioactivity in the milk at 2hr after administration to lactating rats reached levels about 5 times higher than that in plasma, however the radioactivity in milk was not detected at 48hr.
7. In case of repeated administration of ¹⁴C-mofezolac for 7 days, the disposition of radioactivity was almost same as the result after a single dosing, and radioactivity scarcely remained in any tissues after the last administration.

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In vivo metabolism of[3, 4-di(4-methoxyphenyl)-5-isoxazolyl]acetic acid (mofezolac) was studied in mice, rats, dogs and monkeys following intravenous injection or oral administration, and serum protein binding of mofezolac and its metabolites were studied in rats, mice, dogs, monkeys and human.
Obtained results were as follows;
1. Following metabolites were identified in the rat urine and bile and dog bile ; [3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-5-isoxazolyl]acetic acid (3-DM-mofezolac), [4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-5-isoxazolyl]acetic acid (4-DM-mofezolac), [3, 4-di(hydroxyphenyl)-5-isoxazolyl]acetic acid (3, 4-DM-mofezolac), 4-[4-(4-methoxyphenyl)-5-carboxymethyl-3-isoxazolyl]phenyl hydrogen sulfate (3-DM-mofezolac-sulfate), 4-[(4-hydroxyphenyl)-5-carboxymethyl-3-isoxazolyl]phenyl hydrogen sulfate (3, 4-DM-mofezolac-sulfate), β-D-glucopyranuronic acid 1-[3, 4-di(4-methoxyphenyl)-5-isoxazolyl]acetate (mofezolac-glucuronide).
2. After administration to various animal species, plasma levels of mofezolac reached C_max rapidly except monkeys. Area under concentration time curve (AUC) of mofezolac shows the species related differences with the highest AUC value found in dogs. Main metabolite in mice and monkeys plasma were 3-DM-mofezolac and 3-DM-mofezolac and 3-DM-mofezolacsulfate was found only in rats. In dogs plasma only a small quantities of metabolites were observed in the plasma. AUC of 3-DM-mofezolac-sulfate in male rats was about three times higher than female rats.
3. After oral administration of mofezolac to rats, the residue of mofezolac in the stomach was about 60% at 0. 5hr, 33% at 2hr. And at 8hr, the residue in the stomach was slightly detected. In the small intestine, its content consisted mainly of 3-DM-mofezolac-sulfate. In the large intestine, the content of 3-DM-mofezolac was increased when compared with that of the small intestine.
4. After oral administration, main metabolites found in the urine were 3-DM-mofezolac in mice, 3-DM-mofezolac and 3-DM-mofezolac-sulfate in rats, 3-DM-mofezolac and unchanged drug in monkeys, and unchanged drug in dogs. Total amount of urinary excretion was the lowest in dogs among examined animal species.
5. In the feces after oral administration, main metabolites were 3-DM-mofezolac in mice and rats, and unchanged drug in dogs.
6. Mofezolac, 3-DM-mofezolac and 4-DM mofezolac were strongly bound to serum proteins of all species studied. Mofezolac was mainly bound to albumin of human serum.
7. After administration to rats, total amount excreted with bile was about 39% in bile within 24 hours. Main metabolite was 3-DM-mofezolac-sulfate.

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We studied the factors related to species and sex difference contributing to metabolic patterns of[3, 4-di(4-methoxyphenyl)-5-isoxazolyl] acetic acid (mofezolac) in vitro, and the metabolic pathway determined after administrations of metabolites of mofezolac. Also the metabolism of mofezolac in germ free rats, and the in situ absorption rates using recirculation perfusion of mofezolac and the metabolites were studied.
1. Mofezolac demethylase activities in monkeys and rats were highest among investigated animals, following by the activity in mice. The activity in the dog was about 10 times lower than that in mice. Sex difference in mofezolac demethylase activity was not observed in the rats. UDP-glucuronatemofezolac glucuronosyltransferase activities in the monkey and the dog were high, and that in the rat was about 1/3 lower than that in the monkey and the dog.
2. Mofezolac sulfotransferase activity in rats cytosol was much higher than the activities in other investigated animals. Sex deference was observed in rats ; the activity in male rats was about 3 times higher than that in female rats. Therefore, the total amount of sulfoconjugate of[3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-5-isoxazolyl] acetic acid(3-DM-mofezolac) in vivo reflects the sulfotransferase activity of liver.
3. After administrations of mofezolac metabolites, the main metabolite in bile derived from 3-DM-mofezolac was 4-[4-(4-methoxyphenyl)-5-carboxymethyl-3-isoxazolyl] phenyl hydrogeo sulfate (3-DM-mofezolac-sulfate), and the main metabolite derived from[4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-5-isoxazolyl]acetic acid (4-DM-mofezolac) was[3, 4-di(hydroxyphenyl)-5-isoxazolyl] acetic acid (3, 4-DM -mofezolac-sulfate). These results explain that 3-(4-methoxyphenyl) was desmethylated easier than 4-(4-methoxyphenyl). No sulfoconjugate of 4-DM-mofezolac was formed after administration of 4-DM-mofezolac. This result suggested that sulfoconjugate was not formed by binding of a sulfate directly to OH in the phenyl group on the side of 4-position of isoxazol.
4. The main fecal metabolite in SPF rats was 3-DM-mofezolac, while in germ free rats was 3-DM-mofezolac-sulfate. This result clarified that 3-DM-mofezolac-sulfate was degraded by intestinal microflora.
5. The absorption rate constant of mofezolac from the small intestine was close to the absorption rate constants of indomethacin or salicylic acid using in situ recirculation perfusion system. In the stomach, mofezolac was absorbed in about 1/2 of that in small intestine when the perfusate was acidic (pH3). The absorption rate constant of 3-DMmofezolac-sulfate was about 8 times lower than the that of mofezolac. 3-DM-mofezolacsulfate was hardly absorbed.

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Metabolism of [3, 4-di(4-methoxyphenyl)-5-isoxazolyl]acetic acid(mofezolac) was studied in rats after oral administration of ¹⁴C-labeled mofezolac.
1. After administration of 14C-mofezolac, more than 90% of the radioactivity present in plasma accounted for mofezolac and identified metabolites, [3-(4-hyd roxyphenyl)-4-(4-methoxyphenyl)-5-isoxazolyl] acetic acid (3-DM-mofezolac), [4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-5-isoxazolyl]acetic acid (4-DM-mofezolac), [3, 4-di(hydroxy-phenyl)-5-isoxazolyl]acetic acid (3, 4-DMmofezolac), 4-[4-(4-methoxyphenyl)-5-carboxymethyl-3-isoxazoly]phenyl hydrogen sulfate (3-DM-mofezolac-sulfate), 4-[4-(4-hydroxyphenyl)-5-carboxymethyl-3-isoxazolylpheny] hydrogen sulfate(3, 4-DM-mofezolac-sulfate).
2. After administration of ¹⁴C-mofezolac, more than 80% of the radioactivity present in urine (0-24hr) or bile (0-6hr) accounted for mofezolac and identified metabolites (3-DM-mofezolac, 4-DM-mofezolac, 3, 4-DM-mofezolac, 3-DM-mofezolac-sulfate and 3, 4-DM-mofezolac-sulfate). The largest quantity of unknown metabolite was only 1.4% of dose. These results suggested that the disposition of mofezolac in rats could be account for identified metabolites.
3. In feces, the radioactivity of identified metabolites contributed to about 50% of total radioactivity.

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The pramacokinetic behavior of four possible enantiomers of loxoprofen was investigated in the rat. Plasma levels of diastereomeric trans-alcohol metabolite after intravenous injection of 1' R-isomers were significantly higher than after equal doses of 1'S-isomers, while those of cis-alcohol after doses of 1' R-epimers were contrarily lower. In vitro protein binding study revealed that 1'-isomers of loxoprofen showed slightly higher affinity to both plasma and liver cytosol that 1'S-isomers. The enantiomeric contents of each alcohol metabolite in biological fluids after oral doses of racemate (loxoprofen sodium) in both the rat and man were quantified using capillary gas-chromatography linked with an electron ionization mass spectrometry. Alcohol metabolite of loxoprofen in rat plasma was exclusively counted as 2'S-isomers, i. e. trans-(1'R, 2'S)-and cis-(1'S, 2'S)-enantiomer, while minor amounts of their antipodes, i. e. trans-(1' S, 2'R)-and cis-(1' R, 2'R)-alcohol, were excreted in human urine.

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