The pharmacokinetics of Loprinone hydrochloride, a new cardiotonic agent, was investigated after a single intravenous administration of ¹⁴C-labelled compound to male rats.
1. After a single intravenous administration of ¹⁴C-Loprinone hydrochloride to rats, the plasma level of radioactivity rapidly decreased biexponentially, with the corresponding half-lives of 9.7 min and 3.6 hr.
2. Radioactivity was distributed rapidly in all tissues. A high level of radioactivity was observed in the liver and kidney, followed by the duodenum. The tissue levels of radioactivity decreased with half-lives similar to that in blood. Similar distribution profiles were observed with whole body autoradiography, and at 96 hr after dosing, the level of radioactivity in all tissues was very low reaching the detection limit.
3. Loprinone hydrochloride was hardly metabolized. In the urine and feces, the unchanged form was mainly found, however, small amount of metabolites, amine form and enol-O glucuronide of unchanged form, were also detected.
4. Biliary excretion of radioactivity was 46.3% of dose within 24 hr after dosing.
5. Within 24 hr after dosing, the excretion of radioactivity was 43.0 and 47.2% of dose in urine and feces, respectively, and the total excretion of radioactivity was 97.2% of dose within 96 hr.

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Transfer of radioactivity into the fetus and milk after a single intravenous administration of ¹⁴C-Loprinone hydrochloride to pregnant or lactating rats were investigated.
1. On day 12 and 19 of gestation, the tissue levels of radioactivity in the fetus at 5 min after dosing were lower than the plasma levels of radioactivity in the maternal rat. But the elimination of radioactivity in the fetus was slower than that in the maternal plasma.
2. In the fetus on day 19 of gestation, the levels of radioactivity in the kidney, liver and gut were higher than those in the other tissues.
3. The elimination of radioactivity from maternal tissues except liver, kidney, uterus and placenta, was rapid. But 24 hr after dosing, the levels of radioactivity in all tissues were very low.
4. In the fetus on day 12 and 19 of gestation, almost all of radioactivity corresponded to the unchanged form.
5. The milk-to-plasma co ncentration ratio reached the maximum value of 97.1 at 4 hr after dosing. The disappearance of the radioactivity from the milk was slower than that from the maternal plasma. And small amount of radioactivity was detected in the milk at 48 hr after dosing.
6. The radioactivity in the milk consisted mainly from the unchanged form.

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The pharmacokinetics of Loprinone hydrochloride, a new cardiotonic agent, was investigated after a single intravenous administration of ¹⁴C-labelled compound to dogs.
1. After a single intravenous administration of ¹⁴C-Loprinone hydrochloride to dogs, the plasma level of radioactivity rapidly decreased in biexponential manner, with the respective half-lives of 23 min and 5.1 hr.
2. Radioactivity was rapidly distributed to tissues after a dosing. A high level of radioactivity was detected in the kidney and the bile. Radioactivity from all tissues, except choroidea and retina, was rapidly eliminated. And 96 hr after dosing, the levels of radioactivity in all tissues were very low, near the detection limit.
3. Two metabolites of Loprinone hydrochloride were indentified as amine form and enol-O-glucuronide of mother compound in the urine after dosing.
4. Loprinone hydrochloride was hardly metabolized. In the liver, kidney, heart, lung, over 90% of radioactivity corresponded to the unchanged form at 5 min and 1 hr after dosing. And in the urine and feces, the unchanged form was mainly found, however a small amount of metabolites, amine form and enol-O-glucuronide of unchanged form were also detected.
5. Radioactivity, excreted within 24 hr, accounted for 44.7 and 50.1% of dose in urine and feces, respectively, and the total excretion of radioactivity was 99.7% within 96 hr.

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Plasma levels of L-thyroxine (T4), liothyronine (T3) and thyroid-stimulating hormone (TSH), plasma protein binding of T4 and drug-metabolizing activities of liver microsomes were studied in thyroidectomized rat (Tx-R) treated with T4-Na (30 μg/kg, p. o.).
1. The plasma leve ls of T4 in Tx-R treated with T4-Na were similar to those in euthyroid rat (Eu-R) treated with vehicle.
2. The C_max of T4 occurred 8 hr after a single oral administration and plasma levels decayed with the T_1/2 of 58.2 hr.
The bioavailability of T4 was 34.7 %.
3. The elevated TSH due to th yroidectomy decreased to the level of Eu-R during consecutive administration of T4-Na.
4. The growth rates in Tx-R during consecutive administration of vehicle and T4-Na for 21 days were 0.2 and 2.8 g/day, respectively.
5. The amount of T4 bound to plasma protein increased by thyroidectomy and then decreased during consecutive administration of T4-Na.
6. Thyroidectomy did not affect the cyt. P-450 in liver microsomes, while the cyt. b5 increased and NADPH-cyt. c reductase, aminopyrine N-demethylase and arylhydrocarbon hydroxylase activities were decreased. Consecutive administration of T4-Na slightly improved those affections.

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After administration of 0.01% levothyroxine sodium (T4-Na) powder (TZ-T4 : p.o.) and a solution of T4-Na (p.o. and i.v.) to hypothyroid dogs (Tx-D) and euthyroid dogs (Eu-D), the plasma levels of L-thyroxine (T4), liothyronine (T3) and thyroid-stimulating hormone (TSH) were determined by radioimmunoassay. The amount of L-thyroxine bound to plasma protein and the urinary excretion of T4 were studied in Tx-D.
1. TSH level was increased in Tx-D 3 to 7 times higher than in Eu-D for 7-12 days after thyroidectomy.
2. T4 level in Tx-D after a single oral administration of TZ-T4 (100 mg/kg) was similar to that of Eu-D treated with water.
3. A single oral administration of TZ-T4 gave the dose-dependent plasma half-life of T4. These results suggested the excretion of excess T4 as a physiological function.
4. A single oral administration of TZ-T4 (100 mg/kg, corresponding to 10 μg/kg as T4-Na) gave about the same bioavailability as that of T4-Na solution (10 μg/kg).
5. T4 level reached the plateau after consecutive administration of TZ-T4 (100 mg/kg/day, 7 days). T3 level was unchanged for 21 days. TSH level was attenuated to one-half (8.3 ng/ml) of the initial value, though still higher than Eu-D (1.5 ng/ml).
6. The amount of T4 bound to plasma protein was slightly increased by thyroidectomy.

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The plasma concentration, tissue distribution and excretion of radioactivity were investigated after a single intravenous administration of 1 mg/kg of ¹⁴C-YM060 to rats.
1. Whole blood radioactivity decreased bi-phasically with terminal elimination half life (t_1/2) of 78.0 min. Plasma radioactivity showed steady levels up to 15 min after dosing, then decreased with a t_1/2 of 79.8 min. Plasma unchanged drug concentrations decreased bi-phasically with a t_1/2 of 36.6 min. AUC_0-∞ values for whole blood radioactivity, plasma radioactivity and unchanged drug were 398.7 ng equiv. ·h/ml, 412.6 ng equiv. ·h/ml and 123.6 ng·h/ml, respectively.
2. Radioactivity distributed quickly into various tissues, showing a peak concentration at 5 min after dosing in most tissues. Radioactivity levels were highest in the kidney, followed by the lung, liver, adrenal, pancreas, hypophysis, submandibular gland, stomach and small intestine, and were lowest in the brain. Radioactivity disappeared rapidly from tissues, and the levels in most tissues at 24 hr after dosing were less than 1.2% of the peak concentrations.
3. Within 72 hr after dosing, 29.7% and 70.9% of the dosed radioactivity was excreted in the urine and feces, respectively. In bile-duct cannulated rats, 67.2% and 31.1% of the dosed radioactivity was excreted within 72 hr in the bile and urine, respectively. Of the radioactivity excreted in the bile, 33.5% was reabsorbed.

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Pharmacokinetic studies on plasm a level, tissue distribution, metabolism and excretion of perindopril erbumine, an ACE inhibitor, were performed in fasting male rats after single oral administration of ¹⁴C-perindopril erbumine (¹⁴C-DW-7950) at a dose of 0.5 mg/kg.
1. The radioactivity in plasma reached the C_max of 88 ng eq./ml at 1 hr and the elimination half-lives were 2.1 hr (2-8 hr) and 34 hr (24-72 hr).
2. After single oral administration, the radioactivity was rapidly distributed to tissues, reaching maximum levels at 1 hr in most tissues. At 8 hr, a high level of radioactivity was detected in the lung, pituitary gland, intestine, kidney and aorta, due to intensive localization of ACE in these tissues. At 168 hr, the level of radioactivity was reduced in all tissues.
3. The radioactivity was excreted within 168 hr into urine and feces at the rate of 39.7% and 58.7% of the dose, respectively. Biliary excretion of radioactivity was 31.2% within 48 hr. The total recoveries from urine, bile and carcass were 75.4% of dose, suggesting good gastrointestinal absorption.
4. After oral administration, an active metabolite, perindoprilat, was found and accounted for most of the total radioactivity in the plasma, lung, liver and kidney, and also in urine and feces.
5. In the study of dose-dependency, linear pharmacokinetics were observed.

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Pharmacokinetic studies on blood level, tissue distribution, metabolism and excretion of perindopril erbumine, an ACE inhibitor, were performed in rats during and after repeated oral administration of ¹⁴C-perindopril erbumine (¹⁴C-DW-7950) at a daily dose of 0.5 mg/kg for 14 days.
1. The blood levels of radioactivity reached the steady state during 5 days and the Css (C_min) on day 5 was 7.09 ng eq./ml at the accumulation factor of 1.1.
2. After repeated oral administration, the radioactivity was mainly distributed in lung, kidney, liver and intestinal tract. The radioactivity in the lung, in which higher ACE activity distributed, was the highest and reached the steady state during 14 days. Elimination of radioactivity from most of tissues was rapid. It is assumed that the accumulation of radioactivity in plexus chorioideus arose from high localization of ACE.
3. Excretion rate in urine and feces during repeated oral administration was almost constant. At 168 hr after the last dosing, the extent of excretion of radioactivity from the body was 33.1% and 69.6%, respectively.
4. After repeated oral administration, an active metabolite, perindoprilat, was found and accounted for most of radioactivity present in the plasma, lung, liver and kidney, and also in urine and feces.

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