³H-TV-02 was administered subcutaneously (0.4μg/kg), in order to investigate the excretion, plasma profiles and distribution.
1. Urinary and fecal excretion of radioactivity within 10 days after administration, was about 18% and 76% of the dose, respectively.
2. Approximately 75% of total administred radioactivity was excreted into bile, in which calcitroic acid and a little of unchanged TV-02 were detected.
3. The plasma levels of the radioactivity in lipid extracts and unchanged TV-02 reached the maximum at 2hr after administration, then underwent two-phase elimination (T_1/2(α)=2.3hr, T_1/2(β)=434.2hr for the radioactivity in lipid extracts and T_1/2(α)=2.2hr, T_1/2(β)=22.3hr for unchanged TV-02). Only 1α, 24(R)25-(OH)₃D₃ was detected as the metabolite in plasma.
4. The concentration of radioactivity (in lipid extracts) in the site of injection decreased rapidly to the same values as that in plasma at 24hr after injection.
The level of radioactivity in liver, small intestine, and kidney were virtually close to plasma level, and those in other tissues were much lower.

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Plasma profiles, tissue distribution and excretion of ³H-TV-02 ([1β-³H]-1 α, 24(R)-(OH)₂D₃) were investigated in rats after repeated subcutaneous adm inistration (7 or 2ltimes) at the dose of 0.4μg/kg/day.
The radioactivity in lipid extracts from plasma consisted of unchanged TV-02 and small amounts of 1, 24(R), 25-(OH)₃D₃ whose vitamin D₃-like activity was weaker than that of TV-02. The maximal plasma levels of radioactivity following administration of the 21st dose were about 1.5times higher after 7 th dose and nearly equal to a single dose.
The unchanged TV-02 was rapidly eliminatdd from the injection site, liver, small intestine and adipose tissue in which the levels of radioactivity were higher than in plasma after 21st administration.
Urinary and fecal excretion amounted to 10.8% and 87.6% of the total dose of radioactivity during and after 2ltimes repeated administration, respectively.

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The excretion, plasma profiles and tissue distribution of ³H-TV-02 ([1β-³H]-1α, 24(R)-(OH)₂D₃) were investigated in rats after a single and continuous (7days) transcutaneous application.
After a single application (0.4μg/100mg ointment/head), the respective recovery of radioactivity in urine and feces during 11days was 3.6 and 26.2% of the dose. Biliary excretion of radioactivity during 32hrs accounted for 32.5 % of the dose.
The plasma concentration of radioactivity in lipid extracts reached a maximum after 2hr and declined slowly during the application, while after the withdrowal of ointment the elimination was fast.
The level of radioactivity at the application site, practically originating from TV-02, corresponded to more than 6800pg/g tissue during the application. The distribution of radioactivity usually was significant in liver, small intestine and kidney being conceivably related to their disposition.
After repeated application (0.4μg/100mg ointment/hdad/day for 7days), the plasma level were slightly lower and the tissue distribution was almost the same in comparison with the single application.

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₃H-TV-02([1β-³H]-1α, 24(R)-(OH)₂D₃)was given to non-pregnant, pregnant and lacting rats by a single subcutaneous administration (0.4μg/kg).
1. Plasma profiles : Plasma levels of the radioactivity in lipid extracts and unchanged TV-02 reached the maxima after 2hr, then was eliminated in two -phasic fashion. 1α, 24(R)25-(OH)₃D₃ was detected as a main metabolite in plasma.
2. Foeto-placental transfer : The radioactivity in lipid extracts from the fetus on the day 19 was nearly equal to that on the day 14 of gestation.
The concentration of radioactivity (lipid extracts) in the fetus was much lo wer than that in maternal plasma or placenta.
3. Excretion into milk : The radioactivity was detected in lipid extracts from the milk, and milk/plasma concentration ratios were less than 1 within 8hr.
The concentration of unchange TV-02 in the milk was 0.07-0.19 times lower than that in the maternal plasma.

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³H-TV-02([1β-³H]-1α, 24(R)-(OH)₂D₃ was administered subcutaneously (0.4μg/kg) or applied transcutaneously (4μg/2g ointment) to beagle dogs, in order to investigate its plasma profiles and excretion.
After a subcutaneous administration, plasma level of the radioactivity in lipid extracts in which 1α, 24(R)25-(OH)₃D₃ was detected in addition to unchanged TV-02, reached the maximum value of 237 pg eq/ml after 4hr and decreased with apparent half-lives of 17hr and 116hr for α and β phase, respectively. 13% and 81% of radioactivity were excreted in urine and feces, respectively. After a transcutaneous application, the radioactivity in plasma was below the detection limit (Ca. 12pg eq/ml) throughout the sampling period (2 ?? 144hr).

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Absorption, distribution and excretion of ¹⁴C-benidipine · HCl(KW-3049) were studied in rats after a single oral (1.0mg/kg) or intravenous (0.1mg/kg) administration and after repeated oral dosing for 21 days (1mg/kg).
And, plasma unchanged drug levels were determined after repeated oral dosing of KW-3049 (1mg/kg) for 21 days to rats.
1. Plasma levels reached the maximum of 126.4ng equiv./ml (male) or 246.6ng equiv./ml (female) at 0.5hr after oral dosing and the elimination half-lives at the terminal phase were 20.3hr and 30.Ohr in male and female rats, respectively.
2. The highest level of radioactivity was found in the liver at 0.1hr after intravenous dosing. The level of radioactivity in central nervous system was the lowest.
3. Maximum levels in most tissues were reached at 0.5hr after oral dosing. The liver had the highest level of radioactivity except the gastro-intestinal tract. The central nervous system had the lowest level of radioactivity.
4. After intravenous or oral dosing in male rats, 18 or 19% of the dose was excreted in the urine and 84 or 74% of the dose in the feces, respectively. After oral dosing in female rats, 24 and 72% of the dose was excreted in urine and feces, respectively.
5. Biliary excretion of radioactivity was 34% within 48hr after oral dosing.
6. In the case of the repeated oral dosing for 21 days of KW-3049, plasma level of unchanged drug showed no change. The level of radioactivity in plasma after repeated daily dosing of ¹⁴C-KW-3049 increased by repeated dosing untill 14th dosing. Its level after final dose was 1.3 times higher than that after a single dose. Some tissues showed two to three times higher levels of radioactivity after repeated dosing. Excretion of radioactivity into the urine and feces was almost constant during repeated administration, and was 6 and 88%, respectively.

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Absorption and excretion of ¹⁴C-benidipine·HCl (KW-3049) were studied in dogs after oral (0.5mg/kg) and intravenous (0.03mg/kg) administration.
1. Plasma levels reached the maximum of 131.6 ± 4.7ng equiv./ml at 1.3 ± 0.5hr after oral administration (0.5mg/kg) and decreased with the half-life of 28.3 ± 5.1hr at the terminal elimination phase.
2. Plasma levels at 0.1hr after intravenous dosing (0.03mg/kg) was about 21ng equiv./ml and bi-exponentially decreased. The half-life at the terminal elimination phase was 27.1 ± 1.9hr.
3. The binding to serum proteins in vitro was about 99% at 200ng/ml. That in vivo was 69.4 ?? 75.3% during 8hr after oral administration. And that in vivo after intravenous administration was time-dependent and decreased from about 99% to 73%.
4. The radioactivity excreted in urine and feces within 96hr after oral administration was 24.0 ± 1.6% and 73.2 ± 9.8% of dose, respectively. That in urine and feces within 144hr after intravenous administration was 27.2 ± 1.3% and 69.6 ± 5.7%, respectively.
5. The fraction absorbed was assumed to be about 58% based on the comparison of AUC data after intravenous and oral administration, however, from the comparison of urinary excretion data, it was assumed to be about 88%.
6. The radioactivity excreted in bile after intraduodenal administration was 19 ?? 45% within 18 ?? 24hr.

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Absorption, distribution and excretion of ¹⁴C-benidipine•HCl(KW-3049) were studied in monkeys after oral administration (1.0mg/kg).
1. Plasma levels reached the maximum of 157.7±129.5ng equiv./ml at 3.7±3.8hr after oral administration and decreased with the half-life of 93.6±33.7 hr at the terminal elimination phase.
2. The radioactivity extensively distributed to the tissues after oral administration. Relatively high radioactivity was found in the liver, kidney and prostate. The radioactivity in most tissues decreased proportionally to that in plasma.
3. The radioactivity excreted in urine and feces within 120hr after oral administration was 20.9±5.2% and 76.1±7.0% of dose, respectively.

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¹⁴C-Benidipine·HCl (KW-3049) was administered orally at a dose level of 1mg/kg to pregnant (12 and 19 th day of gestation) Wistar rats. The tissue localization of the radioactivity was visualized by whole body autoradiography or measured after dissection. The radioactivity level in the fetus was less than one-third of that in the maternal plasma and disappeared rapidly. Radioactivity level in the fetal brain was higher than that in the maternal brain. ¹⁴C-KW-3049 was also administered orally at a dose level of 1 mg/kg to lactating Wistar rats (14 th day after delivery). The concentrations of radioactivity in the milk were almost same as that in the maternal plasma.

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Plasma levels of KW-3049 were determined after single oral and/or intravenous administration to male and female rats, dogs and monkeys.
1. When KW-3049 was administered to male rats intravenously at the doses of 30, 100 and 300μg/kg, the plasma levels of KW-3049 declined bi-exponentially with the half-lives of 36.4, 29.8 and 28.2 min, at the terminal elimination phase, respectively.
2. When KW-3049 was administered to female rats intravenously at the doses of 100μg/kg, the plasma levels of KW-3049 were similar to those of male rats and declined bi-exponentially with the half-life of 30.1 min at the terminal elimination phase.
3. After oral administration of KW-3049 to male rats at the doses of 1, 3 and 10mg/kg, the plasma levels reached the maximum of 2.4±0.3, 19.5±6.2 and 103.1±41.3ng/ml at 0.25 ?? 0.5hr, respectively, and declined exponentially with the respective half-lives of 2.1, 2.8 and 4.2 hr. Bioavailability of each dose was 4.3, 6.8 and 25.6%, respectively.
4. After oral administration of KW-3049 to female rats at the doses of 1, 3 and 10mg/kg, the plasma levels reached the maximum of 5.7±3.2, 64.7± 49. 371.7±187.8ng/ml at 0.25 ?? 0.5hr, respectively, and declined exponentially with the respective half-lives of 1.7, 2.3 and 4.1 hr. Bioavailability of each dose was 11.0, 23.5 and 95.9%, respectively.
5. When KW-3049 was administered to male beagle dogs intravenously at the doses of 3, 10 and 30μg/kg, the plasma levels of KW-3049 declined bi-exponentially with the half-lives of 69.1, 81.3 and 259.8min, at the terminal elimination phase, respectively.
6. After oral administration of KW-3049 to male beagle dogs at the doses of 0.5, 1.0 and 1.5mg/kg, the plasma levels reached the maximum of 1.6±0.8, 9.8±1.5 and 25.9±5.1 ng/ml at 0.5 ?? 4hr, respectively, and declined exponentially with the respective half-lives of 1.6±0.5, 3.1±2.1 and 4.0±1.3hr. Bioavailability of each dose was 2.5±1.2, 8.3±3.7 and 17.9±3.5%, respectively.
7. After oral administration of KW-3049 to male monkeys at a dose of 1 mg/kg, the plasma levels reached the maximum of 21.3±23.0 ng/ml at 0.7±0.3 hr and declined exponentially with the respective half-life of 4.7±1.2 hr.

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