In order to clalify the species difference in metabolism of MCI-186, the identification of metabolites, urinary excretion rates of unchanged MCI-186 and its metabolites, and in vitro metabolism were investigated in rats, dogs and human.
1. Main metabolites of MCI-186 were sulfate and glucuronide of MCI-186 in all species. In the urine of rats and dogs, excretion rates of sulfate were higher than those of glucuronide, however in the urine of human, excretion rate of glucuronide was higher than that of sulfate, therefore species difference was observed in urinary excretion.
2. Urinary excretion was the main excretion route in all species. Excretion rates of the unchanged MCI-186 to urine were less than 3 % of dose. In dogs and human, urinary excretion can be mostly explained by excretion of unchanged MCI-186, and its sulfate and glucuronide. However in rats, unknown metabolites were present at higher rates of 20 ?? 27% of the urinary radioactivities. And sex difference in urinary excretion was not observed mostly in rats.
3. Activities of formation of MCI-186 sulfate were higher than those of MCI-186 glucuronide at in vitro metabolism of MCI-186 with liver S9 of rats and dogs. And both activities were higher in male rats than in female rats.

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In order to clarify the metabolic fate of MCI-186 in rats, blood and plasma levels, distribution, metabolism and excretion were investigated after a single intravenous administration of ¹⁴C-MCI-186 to male and female rats.
1) After intravenous administration of ¹⁴C-MCI-186 (0.3, 2, 5.2 mg/kg), blood levels of radioactivity decreased relatively rapidly, and the areas under the concentration time curves (AUC_0→∞) correlated well with doses (r=0.987).
2) Plasm a levels of radioactivity and the unchanged MCI-186 decreased rapidly and biphasically after intravenous administration of ¹⁴C-MCI-186 (2 mg/kg). In plasma, sulfate of MCI-186, unchanged MCI-186 and glucuronide of MCI-186 were present in higher levels and their AUC_0→∞ accounted for 30 ?? 33%, 13 ?? 15% and 6 % of the AUC_0→∞ of plasma radioactivities, respectively.
3) Distribution of radioactivity to tissues was rapid, and disappearance of radioactivity was also rapid except from the blood vessel (aorta). Disappearance of radioactivity from blood vessel was very delayed. And sex difference was observed in these disappearance, that is, in female rats radioactivities in tissues decreased more rapidly than in male rats. Concentrations of radioactivity in brain at 5 min after administration were low corresponding to 1/16 ?? 1/18 of the concentrations in plasma, and site specific distribution in brain was not observed. Most of radioactivity in brain consisted with unchanged MCI-186, and most of radioactivity in kidney consisted of sulfate of MCI-186.
4) Excretion of radioactivity was rapid and complete in both male and female rats. Eighty six to 92% of the dosed radioactivity was excreted to urine, therefore main excretion route was urinary excretion. Biliary excretion was 4.6% of the dose and it is possible that most of it was subjected to entero-hepatic circulation.

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During and after a single or repeated intravenous administration of ¹⁴C-MCI-186 (2 mg/kg/day) for 7, 14 and 21 days to male rats, blood and plasma levels, distribution, metabolism, excretion and accumulation of MCI-186 were investigated.
1) Tissue levels of radioactivity at 5 min after each dosing during repeated administration were constant except in the blood vessel (aorta). Tissue levels of radioactivity at 24 hr increased to 2 ?? 9 times by 21 days repeated administration, but they were saturated after 7 or 14 days repeated administration. Transfer rates to blood cells also increased by repeated administration. Decrease of radioactivity from tissues was delayed after 21 days repeated administration, especially from the blood vessel (aorta).
2) Concentrations of the unchanged MCI-186 and metabolites in plasma, brain, liver and kidney at 5 min after each dosing during repeated administration were not significantly changed by repeated administration, however concentrations of the unchanged MCI-186 in the liver showed a tendency to decrease by repeated administration.
3) During 21 days repeated administration, radioactivities were excreted to urine and feces constantly, and until 192 hr after final dosing of repeated administration, 88% and 10% of the total dose were excreted to urine and feces, respectively. Total excretion extent reached 99% of the dose, therefore remaining fraction in the rat body was suggested to be minimal. Urinary excretion of the unchanged MCI-186 and metabolites were also not affected by repeated administration, except the excretion rates of MCI-186 glucuronide those seemed to decrease by repeated administration.

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Feto-placental transfer and excretion into milk were investigated in pregnant and nursing female rats after a single intravenous administration of ¹⁴C-MCI-186 (2 mg/kg).
1) In pregnant rats, on day 14 of gestation, the level of radioactivity in fetus was 0.56 μg/g at 5 min after administration, that was low at 1/23 of the maternal plasma concentration, then decreased rapidly.
2) In pregnant rats, on day 19 of gestation, the level of radioactivity in fetus was 0.91 μg/g at 5 min after administration, that was 1/9.9 of the maternal plasma concentration, and the transfer rate to fetus increased by increasing the gestation days. In fetus, the levels of radioactivity in intestine, kidney, liver and brain showed high levels in the order. About 44% and 23% of the radioactivity in fetus consisted of sulfate and glucuronide of MCI-186, respectively. Glucuronide was transfered to fetus more easily than sulfate. Decrease of radioactivity from fetus, especially from fetal intestine, was delayed, therefore concentration of radioactivity in fetus at 24 hr after administration was 2 times higher than that in maternal plasma.
3) Concentrations of radioactivity in the milk reached maximum (0.71 μg/ml, at 15 min after administration. Milk concentrations decreased more slowly than plasma concentrations, and ratios of milk to plasma concentrations increased parallel with course of time. The radioactivity in the milk consisted mainly of MCI-186 sulfate.

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Blood or plasma levels, metabolism and excretion were investigated after a single intravenous administration of ¹⁴C-MCI-186 (2 mg/kg) to male dogs.
1) Decrease of radioactivity from whole blood was more delayed than from plasma, and transfer rates to blood cells increased parallel with the course of time.
2) Unchanged MCI-186 in plasma decreased rapidly with the half-lives of 0.07 hr (t_1/2α) and 0.70 hr (t_1/2β). Areas under the concentration time curves (AUC_0→∞) of unchanged MCI-186, sulfate and glucuronide of MCI-186 in plasma consisted 5.2%, 61.1% 16.2% of the AUC_0→∞ of the radioactivity in plasma, respectively.
3) The dosed radioactivity was excreted to urine and feces until 120 hr after administration, in 84.1% and 13.2%, respectively, and main excretion route of MCI-186 was urinary excretion in dogs. 2.8%, 66.2% and 9.4% of the dosed radioactivity were excreted to urine as the forms of unchanged MCI-186, sulfate and glucuronide of MCI-186, respectively.
4) In dogs, the clearanc e of unchanged MCI-186 and percentages of MCI-186 sulfate to total radioactivity in plasma and urine were higher than those in rats. And unknown metabolites observed in dogs, accounted for a small fraction.

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The absorption, distribution and excretion of ³H labeled ST-630 [(+)-(5Z, 7E)-26, 26, 26, 27, 27, 27-hexafluoro-9, 10-secocholesta-5, 7, 10(19)-triene-1α, 3β, 25-triol], a new fluorine-substituted analog of 1α, 25-dihydroxyvitamin D₃, were studied after single oral administration at a dose of 1 or 10 μg/kg in male and female rats.
1. The serum levels of radioactivity reached a maximum (C_max) at about 2 hr after dosing at a dose of 1 μg/kg to male and female rats, and then declined with a half life (t_1/2) of 2.8 day (24 ?? 168 hr after dosing) or 2.0 day (24 ?? 168 hr after dosing) in male and female rats, respectively. The serum concentrations of ST-630 reached a C_max at 2 hr after dosing and then declined with a t_1/2 of 1.0 day (male, 24 ?? 72 hr after dosing) or 0.9 day (female, 24-48 hr after dosing). Most of the radioactivity at 2 hr after dosing was found to be ST-630, and, the ratio of ST-630 to the radioactivity was decreased with time.
2. High levels of radioactivity were detected in the small intestine at 2 ?? 24 hr and in the kidney at 24 hr after dosing at a dose of 1 μg/kg to male and female rats. The autoradiograms of the small intestine showed that the radioactivity was distributed selectively at the intestinal mucosa besides the intestinal contents at 2 ?? 24 hr after dosing with 10 μg/kg to male rats.
3. The ratios of non-volatile radioactive component excluding tritiated water to total radioactivity (dry/wet) in many tissues were decreased with time. However little decrease of dry/wet in the liver, kidney and fat were observed at 168 hr after dosing.
4. Excretion of radioactivities in the urine, feces and expired air were 4.8%, 86.1% and 1.2% respectively for male rats, and 5.0%, 87.9% and 0.8% respectively for female rats within 168 hr after dosing of 1 μg/kg.
5. The t_1/2 and AUC of radioactivity in male rats were about 1.4 times higher than those in female rats. However there were no marked differences in pharmacokinetics of ST-630 between male and female rats. No significant sex-related differences in the distribution and excretion of radioactivity were observed.
6. In bile-duct cannulated rats, 16% of dosed radioactivity was excreted into the bile for 72 hr after dosing at 1 μg/kg, and then approximately 40% of radioactivity presented in the bile was reabsorbed within 48 hr.

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The metabolism of ³H labeled ST-630 [(+)-(5Z, 7E)-26, 26, 26, 27, 27, 27-hexafluoro-9, 10-secocholesta-5, 7, 10(19)-triene-1α, 3β, 25-triol], a new fluorine-substitated analog of 1α, 25-dihydroxyvitamin D₃, was studied after single administration in rats.
1. After oral administration to rats, the ST-630 was detected as the main component and a small amount of ST-232, C23-hydroxylated bioactive metabolite of ST-630, was also detected in serum.
2. After oral administration to rats, ST-630, ST-232 and calcitroic acid were exc reted into the bile asglucuronides or other conjugates.
3. In the small intes tine and kidney, the target organs of 1α, 25-dihydroxyvitamin D₃, the major components of radioactivity were ST-630 and ST-232. At 24 hr after oral administration, ST-232 was detected predominantly in these tissues.
4. The metabolic pat hway of ST-630 in rats was partially similar to that of 1α, 25-dihydroxyvitamin D₃, which is finally metabolized to calcitroic acid and glucuronides. However, ST-630 was mainly metabolized to the bioactive metabolite, ST-232, which was retained in target tissues, causing greater potency of ST-630 than 1α, 25-dihydroxyvitamin D₃.

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The serum concentrations of ₃ labeled ST-630 [(+)-(5Z, 7E)-26, 26, 26, 27, 27, 27-hexafluoro-9, 10-secocholesta-5, 7, 10(19)-triene-1α, 3β, 25-triol], a new fluorine-substituted analog of 1α, 25-dihydroxyvitamin D₃, were determined in male rats after single oral or intravenous administration at a dose of 0.3, 1.0 or 3 μg/kg. The distribution, metabolism and excretion of ³H labeled ST-630 were also studied in male rats after single intravenous administration at a dose of 0.3 μg/kg.
1. The serum levels of radioactivity reached a maximum (C_max 614 pg eq./ml) at 2 hr after oral dosing at a dose of 1 μg/kg, and then declined with a half life (t_1/2) of 1.6 day (24-168 hr after dosing), the AUC_{[0-168 hr]} was 9.48 ng eq.·.hr/ml. The serum concentrations of ST-630 reached a C_maxs (620 pg/ml) at 2 hr after oral dosing and then declined with a t_1/2 of 20 hr (24-72 hr after dosing), the AUC_{[0-72 hr]} was 6.64 ng·hr/ml.
2. C_max and AUC of the serum levels of radioactivity and ST-630, after oral dosing showed a good linearity to dose ranging from 0.3 to 3 μg/kg.
3. C_max and AUC of radioactivi ty and ST-630 after oral dosing to fasting rats were about half of those observed in non-fasting rats.
4. After intravenous dosing at a dose of 0.3 μg/kg, the serum levels of radioactivity declined with a t_1/2 of 1.4 day (24-168 hr after dosing), the AUC_{[0-168 hr]} was 15.3 ng eq.·hr/ml, and the serum concentrations of ST-630 declined with a t_1/22 of 25 hr (24-120 hr after dosing), and the AUC_{[0-120 hr]} was 13.9 ng·hr/ml. The bioavailability was estimated to be about 17%.
5. The tissue distribution pattern of rad ioactivity after intravenous administration was not significantly different from that after oral dosing, except that the level of the small intestine was lower than that after the oral dosing.
6. The main component of radioactivity in the kidney at 24 hr after intravenous dosing was ST-232, a bioactive metabolite. However, in the small intestine at 24 hr after intravenous dosing, ST-630 was mainly detected.
7. Within 168 hr after intravenous dosing at 0.3 μg/kg, 8.5% and 71.2% of dosed radioactivity were excreted in the urine and feces, respectively.

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