Plasma levels of NZ-105 were determined after an intravenous and a single oral administration to rats and dogs.
1. When NZ-105 was administrated to rats and dogs intravenously at the doses of 1.0 and 0.3 mg/kg respectively, the plasma levels of NZ-105 declined biexponentially with the half-lives of 1.35 and 1.03 hr at the terminal elimination phase, respectively.
2. After oral administration of NZ-105 to rats at the doses of 5, 10 and 20 mg/kg, bioavailability of each dose was 19.5, 25.0, 23.9%, respectively.
3. When NZ-105 was administrated to unfasted rats orally at the dose of 10 mg/kg, the bioavailability was 10.0%. The absorption of NZ-105 was affected by food consumption.
4. After oral administration of NZ-105 to dogs at the doses of 2, 5 and 10 mg/ kg, bioavailability of each dose was 5.1, 5.6, 4.9%, respectively.

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Metabolism of ataprost [5(E)-15-cyclopentyl-6, 9-deoxa-6, 9α-methylene 16, 17, 18, 19, 20-pentanor-PGI₂, OP-41483], a prostacyclin derivative, was investigated in rats. After intravenous administration of [³H]ataprost, its metabolites in urine, bile and plasma were analyzed by TLC, and identified their structures by GC/MS spectrometry, ¹H-NMR spectroscopy and also co-chromatography with synthetic standards. The results were as follows:
1. The unchanged ataprost was not detected in urine and bile.
2. Ataprost was metabolized through oxidation of hydroxy group at C-15 position, reduction of double bond, consecutive β-oxidation of aside chain, hydroxy lation of cyclopentane ring at C-18 position and glucuronidation.
3. The major metabolites thus identified in plasma, urine and bile were 13, 14-dihydro-2, 3, 4, 5-tetranor-15-oxo-ataprost (PM3), 13, 14-dihydro-18-hydroxy-2, 3, 4, 5-tetranor-15-oxo-ataprost (UM1 and UM2) and glucuronic acid conjugate of 2, 3, 4, 5-tetranor-ataprost (BM1), respectively.

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The placental transfer, excretion into milk and site of absorption of ¹⁴C RU44570 were investigated in normal rats and male rats with ligated loops of gas trointestinal tract. The absorption, distribution, metabolism and excretion of ¹⁴C-RU44570 were examined during and after repeated oral administration to male rats at a daily dose of 1 mg/kg for 21 days. In addition, the metabolism of ¹⁴C-RU44570 in male dogs was studied after a single oral administration at a dose of 1 mg/kg.
1. In pregnant rats, receiving orally 1 mg/kg of ¹⁴C-RU44570 on the 18th days gestation, the level of radioactivity in fetus was lower than that in maternal plasma, and then ratio of the radioactivity was only 0.01% of the dose. In most of fetal tissues, the radioactivity levels decreased rapidly, however, relatively higher level was observed in the lung at 24 hr after the dosing.
2. The maximum concentration of radioactivity in the milk was found at 8 hr following oral administration of ¹⁴C-RU44570 at 1 mg/kg to lactating rats. The radioactivity concentration decreased with a half-life of 43 hr.
3. In a study of gastrointestinal absorption in situ, the most of ¹⁴C-RU44570 was found to be absorbed from duodenum and jejunum.
4. During repeated daily oral administration, plasma concentration of radioactivity at 24 hr did not increase significantly after the 7th dose. The elimination half-life of plasma radioactivity after the final dosing was comparable to that after the 1st dose. The radioactivity in most of tissues reached a steady state after the 7th or 14th dose during repeated administration. At 672 hr after the final dose, higher level of radioactivity was observed in the lung, while the concentration in other tissues decreased to lower level or even below the detection limit.
5. In plasma, urine, feces, bile or tissues, RU44403, which is a pharmacologically active form, was mainly found after both of single and repeated oral administration to male rats. Unchanged compound, RU44570, was not observed in plas ma and tissues. In addition, any conjugates of the metabolites were not found.
6. In plasma, urine or feces of male dogs, RU44403 was found as a major metabolite, however, RU44570 was also observed in dog plasma.

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The effect of food intake on the bioavailability of vamicamide, a new anticholinergic drug, was studied in six healthy male volunteers. Each subject, in a two-way crossover manner, was given a single 18-mg oral dose of vamicamide after overnight fasting or 30 minutes after a standard breakfast. There were no significant differences in the area under the serum concentration-time curve, the maximum serum concentration, the time to reach the maximum serum concentration, elimination half-life, renal clearance or urinary recovery between the fasting and non-fasting state. These results showed that the bioavailability of vamicamide appears to be little affected in the presence of food.

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The pharmacokinetic data of vamicamide, a new anticholinergic drug, collected from healthy male subjects were analysed to estimate population pharmacokinetic parameters.
A total of 48 subjects participated in three single-dose studies and three multiple-dose studies. In the single-dose studies, the subjects were given vamicamide tablets or capsules in doses of 0.7 to 48 mg, and in the multiple-dose studies, doses of 6, 12 or 36 mg two or three times a day for six days. These six studies were conducted independently in two different facilities using the two different dosage forms. Subjects were given the drug after a meal or in a fasting state depending on each study. 931 serum vamicamide concentration data and 143 urinary vamicamide excretion data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis. The pharmacokinetic model used was a one-compartment model with first-order absorption. A linear or nonlinear regression model was used to evaluate the effects of bodyweight, age, dosage form or food intake on the pharmacokinetic parameters of vamicamide.
The mean elimination rate constant (Ke), apparent volume of distribution (Vd/F) and urinary recovery were estimated to be 0.137 hr^-1, 2.24 L/kg and 91.6%, respectively. Vd/F varied linearly with bodyweight. Food intake significantly affected absorption rate constant (Ka) and lag time of absorption (to) but not Vd/F. Ka increased from 1.75 hr^-1 in a fasting state to 2.63 hr^-1 after a meal, and t₀ increased from 0.178 hr to 0.347 hr. These increases, however, did not cause any clinically significant difference in maximum serum concentrations, suggesting that the bioavailability of vamicamide appears to be little affected by food intake. Dosage form and subject age, in the range of 22 to 46 years, had no signifficant effect on the pharmacokinetics of vamicamide. The estimates of in terindividual variabilities were 71.3% in Ka, 12.8% in Ke and 11.7% in Vd/F as a coefficient of variation. The residual variabilities in the serum concentrations and in the urinary excretion were 16.5% and 12.0%, respectively.

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The pharmacokinetics of (-)-(2S, 3R) -2-amino-3-hydroxy) -3 (3, 4-dihydoxy-phenyl)propiconic acid (L-DOPS), the precursor of (-)-norepinephrine (NE), were studied, using ¹⁴C-L-DOPS labelled at C-3 position (10 mg/kg), in rats with renal failure.
After single oral administration of ¹⁴C-L-DOPS (10 mg/kg) to 5/6 partially nephrectomized rats, the serum ¹⁴C halflife (T_1/2) was longer and the maximum concentration (C_max), the area under the curve (AUC_0-48) were 3, 10 times higher than those of the sham-operated rats respectively. Nevertheless, the excretion of radioactivity into urine or feces within 72 hr after administration were not significantly different between nephrectomized and sham-operated normal rats.
L-DOPS, (-)-(2S, 3R)-2-amino-3-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-propionic acid (3-OM-DOPS), 3, 4-dihydroxybenzoic acid (Protocatechuicacid, PA), 4-hydroxy-3-methoxybenzoic acid (Vanillic acid, VA), their conjugates and 3, 4-dihydroxytoluene conjugate were identified as the metabolites present in the serum at 24 hr after single oral administration of ¹⁴C-L-DOPS (10 mg/kg) to completely nephrectomized rats.
VA and PA conjugates were measured as the major metabolites.
¹⁴C levels in major tissues were changed in parallel with ¹⁴C serum levels and no particular ¹⁴C increase in tissue was found in 5/6 partially nephrectomized rats. The radioactivity decreased in tissues rapidly and no tissue with specific ¹⁴C accumulation was observed.
During the consecutive oral administration of ¹⁴C-L-DOPS (10 mg/kg/day) to 5/6 partially nephrectomized rats for 7 days, the ¹⁴C serum levels profile on the 4th day and 7th day were similar to those observed on the 1st day.
After repeated oral administration of ¹⁴C-L-DOPS (10 mg/kg) for 7 days, the elimination rate of ¹⁴C in tissues was slower than that observed on the 1st day, however ¹⁴C decreased below 1.0 μg eg./g. in all tissues at 72 hr and no particular accumulation in any tissue was found.

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The metabolism and disposition of ¹⁴C-quinapril hydrochloride were studied in rats. The compound was mainly absorbed from the small intestine. The extent of absorption was estimated to be between 50 and 65% after an oral dose of 3 mg/ kg in fasting male rats. The plasma level of radioactivity reached a maximum at 0.5 hour, and the terminal half-life was 29.6 hours. Peak levels in plasma (C_max) and the areas under the plasma concentration-time curve (AUC) were proportional to the dose between 1 and 30 mg/kg. In non-fasting condition Cmax decreased, but AUC did not alter. No sex-related differences were observed in pharmacokinetic parameters. High levels of radioactivity were observed in the liver, plasma, kidney, blood and the lung at 0.5 hour after the administration and the levels rapidly decreased in all tissues studied. Radioactivity was slightly detected only in the lung, liver and the kidney at 72 hours after the administration. Similar distribution characteristics were observed with the whole body autoradiograms. Residual radioactivity accounted for 0.1% in the carcasses at 120 hours after the administration. Binding extent of radioactivity to plasma proteins was between 95 and 97%. Radioactivity in plasma was hardly transferred to the blood cells. Quinaprilat, an active metabolite, was mainly detected in the plasma, urine, feces and the bile, but quinapril and other metabolites were hardly detected. Within 120 hours after oral administration of ¹⁴C-quinapril hydrochloride at a dose of 3 mg/kg to male rats, the urinary and fecal excretion of radioactivity were 18.8 and 78.6%, respectively. The excretion of radioactivity in female rats was similar to that in male rats. Within 48 hours after oral administration to bile-duct cannulated male rats, biliary excretion was 43%. Twenty two percents of radioactivity excreted in the bile was reabsorbed from the intestine.

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The tissue distribution and excretion of radioactivity were investigated after a single intravenous administration of 0.3 mg/kg of ¹⁴C-YM175 to rats.
1. YM175, labelled with ¹⁴C, concentrated into the bones a target organ, rapidly after intravenous administration to rats, and remained there for a long period. Though radioactivity level in the kidney was almost equal to that in the bone at 5 min after dosing, the concentration in other tissues/organs was lower than the plasma concentration; the lowest in the brain. Radioactivity disappeared slowly from the spleen, liver, bone marrow, rib and humerus, whereas in other tissues, radioactivity disappeared relatively rapidly.
2. Humerus and rib radioactivity levels decreased bi-exponentially, with t_1/2α alues of 4.8 and 8.9 days, and t_1/2β values 331 and 214 days, respectively.
3. The autoradiography of humerus revealed high levels of radioactivity in the metaphysis followed by the diaphysis and epiphysis, but radioactivity was not detected in the marrow cavity. Radioactivity in the humerus remained at the site of initial localization, and was not found in the portion that grew subsequently. Humerus radioactivity concentrations decreased on decalcification to 0.2-0.6% of that prior to decalcification.
4. Within 168 hr after dosing, 64.5 and 2.5% of the dosed radioactivity was excreted in the urine and feces, respectively. At the end of this period 32.9% of the dosed radioactivity was remained in the carcass, hence total recovery was 99.9%. In bile-duct cannulated rats, 0.8 and 57.0% of the dosed radioactivity was excreted within 48 hr in the bile and urine, respectively.

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The absorption, tissue distribution and excretion of [¹⁴C]finasteride were stu died in male and female rats after oral or intravenous administration. Plasma lev els of intact compound were also measured by HPLC after finasteride administration.
1. After oral administration, [¹⁴C]finasteride was rapidly absorbed and reached C_max (1.23 and 1.38μg/ml) at 1 and 2 hr in male and female rats, respectively. The radioactivity disappeared biexponentially with the T_1/2S of 1.4 and 20 hr in males and monoexponentially with the T_1/2 of 2.2 hr in females. After in travenous administration, Cmax values of 2.54 and 2.20μg/ml were observed at 30 min and 1 hr in male and female rats, respectively. The presence of this peak was observed only in the case of radioactivity, suggesting the formation of a metabolite with a smaller volume of distribution than the parent drug. T_1/2 were similar in both sexes (male, 1.3 hr: female, 1.8 hr). [¹⁴C]Finasteride was well absorbed (male, 81% and female, 100%). The non labeled finasteride study showed that oral bioavailability was similar in both sexes (male, 62% and female, 59%), whereas AUC was about 2 times larger in females and T_1/2 was longer in females after oral administration.
2. Finasteride was absorbed mainly from the intestine.
3. After oral administration of [¹⁴C]finasteride, the maximum concentration in almost all tissues was reached within 1 hr, similar to the plasma peak time (0.5 hr). The radioactivity was especially highly distributed in stomach, liver, and adrenal gland. At 24 hr post dose, the levels in tissues were the same or higher than that of plasma, and then decreased and were lower than 11% of the maxi mum at 72 hr. Similar distribution was observed after intravenous administra tion. The ARG study also supported the above data.
4. [¹⁴C]Finasteride was excreted mainly into bile in both sexes, regardless of the route of administration. More than 94% of the radioactivity was excreted into bile during 48 hr, and approximately 30% of the administered radioactivity was reabsorbed due to entero-hepatic circulation.

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After oral administration of quinapril hydrochloride (3 mg/kg) to rats and dogs, the unchanged drug, its active metabolite (quinaprilat) and the diastereomers of quinaprilat in plasma were simultaneously analyzed using the gas chromato graph-negative ion chemical ionization mass spectrometer.
The obtained results are as follows: (1) In rats, the plasma concentration of quinaprilat reached the maximum (C_max) of 2.48 μg/ml at 0.38 hr after oral administration, and then disappeared with the terminal half-life (t_1/2z) of 33.9 hr. The unchanged drug in plasma was not detected throughout all the time point examined. The bioavailability of quinaprilat was 63.4%.
(2) In dogs, the plasma concentration of unchanged drug reached the C_max of 0.41μg/ml at 0.42 hr and that of quinaprilat reached the C_max of 3.51 μg/ml at 0.92 hr after oral administration. The unchanged drug in plasma quickly disappeared and quinaprilat disappeared with the t_1/2z of 16.8 hr. The bioavailability of quinaprilat was 47.1%.
(3) There were no changes in the configuration of quinapril and quinaprilat after oral administration to rats and dogs.

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The stereoselective pharmacokinetics of the four stereoisomers [FK176 (2R, 4R- and 2S, 4S-isomer) and FK177 (2R, 4S- and 2S, 4R-isomer)] of 4-(dimethylamino)-2-phenyl-2-(2-pyridyl)pentanamide were studied in rats.
1. When racemic FK176 (vamicamide) was orally administered to rats at 10 mg/kg, there were no stereoselective differences in the pharmacokinetics of 2R, 4R and 2S, 4S-enantiomer.
2. When racemic FK177 was orally administered to rats at 10 mg/kg, the mean Cmax and AUC values for the 2R, 4S-enantiomer were 2.0 and 3.0 times greater, respectively, than those for the 2S, 4R-enantiomer.
3. Serum protein binding of four stereoisomers were very low and there was no appreciable difference.
4. Rat hepatic microsomes metabolized 2S, 4R-isomer faster than 2R, 4R-, 2S, 4S and 2R, 4S-isomer. 2S, 4R-isomer was mainly metabolized to aryl hydroxylated metabolite.
5. Eight metabolites, M-I to M-V and M-B to M-D, were isolated from bile samples collected from rats after oral administration of FK176 or 2S, 4R-isomer. The structures of these metabolites were characterized by mass spectrometry and were comfirmed by comparison with reference compounds.
6. Finally, we concluded that the stereoselective differences in serum levels of 2S, 4R isomer were caused by stereoselective hepatic metabolism.

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