Plasma angiotensin II levels were examined in rats, rabbits and dogs after single i.v. administration or i.v. infusion. The plasma concentrations were determined by radioimmunoassay.
1. After single i.v. administration of 0.1, 1.0 and 10.Oμg/kg to male and female rats, the plasma concentrations declined rapidly with half-lives (T_1/2) of 11.9-19.1sec.
2. After single i.v. administration of 1μg/kg to rabbits and dogs, their profiles of plasma concentration-time curve were similar to that of rats, and declined with T_1/2 of 23.4 and 26.8 sec, respectively.
3. After i.v. infusion of 1μg/kg/min for 15min in rats and dogs, the plasma concentrations declined in similar manner as after single i.v. administration. The T_1/2 were regarded to be equal after both administration methods.
4. After consecutive administrations to rats and dogs for 7 days, no significant accumulation occurred in the plasma concentrations. A similar concentration-time curves were obtained between lth and 7th day.
5. After single i.v. administration to nephrectomized rats, the plasma concentration was not different from that of normal rats.
6. In vitro plasma protein binding ratios of angiotensin II in rats, dogs and human were 42.9, 58.3 and 57.9%, respectively. In vivo plasma protein binding ratios were 48.0% in rats at 15sec after single i.v. administration and 60.0% in dogs at 15min after beginning of i.v. infusion.

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The metabolism of angiotensin II (AII) was examined using the plasma and tissue homogenates from rats aged 7 weeks and 13 months.
1. Metabolites of AII present in the rat kidney homogenate were separated and purified by HPLC. These metabolites, identified by the HPLC retention time compared with each standard compound and by the analysis of amino acid components, were angiotensin III (AIII), des-[Asp¹, Arg¹] A II (AII-(3-8)), des-[Asp¹, Arg², Val³] AII (AII-(4-8)) and des-[Asp¹, Phe⁸] AII(AII-(2-7)).
2. In the presence of a high concentration of AII(0.2mM), the degradation rate of AII was in the following order, kidney>liver>lung, In liver and kidney homogenates, the decreasing of AII was associated with rapid increase of AIII, and then moderate incrcase of AII-(3-8) and AII(4-8). Moreover, the decreasing of AIII was accompanied by pronounced generation of tyrosine (Tyr) and phenylalanine (Phe). The degradation rate and metabolic pattern of AII in each tissue homogenate showed no age-related differences between 7-week-and 13-month-old rats.
3. When a low concentration of tritium-labeled AII (17nM) was added to plasma and kidney homogenate, the degradation rate of AII and the production rate of Tyr (expressed per protein contents) in kidney homogenate were 200- and 350- fold higher than those in plasma, respectively.
4. These results on the metabolism of AII suggest that AII was primary metabolized to AIII, then via AII-(3-8), AII-(2-7) and AII-(4-8), rapidly metabolized to free amino acids. The effect of age on the in vitro metabolism of AII is minimal.

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Intestinal absorption and tissue distribution of water-soluble lignins which had both immunomodulating and antiviral activities were investigated using the isotope tracer techniques. Three types of water-soluble lignins with different molecular weights, i.e., EP3 (av. mol. wt., 3.2 × 10⁵D) and SB1000 (mol. wt., 10³—10⁴D), both of which were fractionated from LEM (an extract of culture medium of Lentinus edodes mycelia), and PLS(purified lignosulfonate, av. mol. wt., 2 × 10⁴D) were used after being labeled with ¹⁴C-HCHO.
After p. o. administration, every [¹⁴C] lignin was absorbed and reached maximum levels in the tissues, especially, kidney cortex, lymph node, liver and vertebra within 6 hr. ¹⁴C-EP3, the sample of the highest molecular weight, showed the lowest absorption, whereas it remained in cortex for a longer period. By summing up the isotope amount in urine and tissues, the absorption extents of ¹⁴C-EP3, ¹⁴C-PLS and ¹⁴C-SB1000 were estimated to be approximately 0.8%, 5.9% and 8.0% of radioactivity, respectively. Absorption and prolonged remain of ¹⁴C-EP3 in the lymph node and vertebra suggest that the in vitro immunological activities of this lignin would be linked to those in vivo.

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The absorption, distribution, metabolism and excretion of Betaxolol were investigated in male and female rats after oral or intravenous administration of ¹⁴C-Betaxolol.
1. After oral administration of ¹⁴C-Betaxolol to male rats, there was a good correlation between the area under time versus concentration curve(AUC_0→∞) of radioactivity in blood and administered doses ranging from 0.5 to 5mg/kg.
2. After intravenous administration (1 mg/kg) of ¹⁴C-Betaxolol to male rats, blood levels of radioactivity decreased rapidly until 30min after dosing, and then increased until 1hr after dosing, followed by the decrease with half-lives of 2.2hr and 21.9hr. Plasma levels of unchanged betaxolol decreased rapidly with half-lives of 0. 28hr (T_1/2α) and 1.18hr (T_1/2β).
3. After oral administration (5mg/kg) of ¹⁴C-Betaxolol to male and female rats, blood levels of radioactivity reached the maxima at 1hr and decreased with half-lives of 1. 52hr and 20. 3hr in male rats, and 1. 34hr and 17. 9hr in female rats, respectively. Plasma levels of unchanged Betaxolol of female rat were significantly higher than those of male rat. The systemic bioavailability in male rats was 7.9%.
4. Radioactivity was excreted completely in urine (83.1%) and feces (15.0%) within 96hr after oral administration to male rats. Cumulative biliary excretion rate of radioactivity was 5. 6% of the dose within 48hr after oral administration.
5. Radioactivity in most tissues reached the maxima at 0.5 or 1hr after oral administration. The tissue levels of radioactivity were higher in the liver, intestinal tract, kidney, lung, adrenal and submaxillary gland than in plasma, and then decreased with the halflives similar to radioactivity in blood.
6. Main metabolite in plasma, urine, feces and organs (liver, kidney, heart and brain) was M-1. Major metabolic route of Betaxolol in rats was oxidation of cyclopropylmethoxyethyl moiety.

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The absorption, distribution, metabolism, excretion and accumulation of Betaxolol were investigated after repeated oral administration of ¹⁴C-Betaxolol (5mg/kg/day) to male rats for 21 days. The effect of Betaxolol on the hepatic drug-metabolizing enzyme activities was also investigated after repeated oral administration of Betaxolol (5 and 20mg/kg/day) to male rats for 21 days.
1. Blood levels of radioactivity at 2hr after each dosing remained almost constant since the 1st day. During the repeated oral administration of ¹⁴C-Betaxolol, blood levels of radioactivity at 24hr after each dosing continued to increase till the 14th day. After the 14th administration, blood levels of radioactivity reached to the plateau. Blood levels of radioactivity after repeated oral administration decreased more slowly than that after a single administration.
2. The excretion rates of radioactivity in the urine and feces were nearly constant during the period of repeated administration of ¹⁴C-Betaxolol, and were similar to those after a single administration. Within 24hr after the last dosing, 80% of the administered radioactivity was recovered in urine and 18.8% in feces.
3. The tissue levels of radioactivity at 24hr after each dosing increased gradually until the 14th administration, followed by remaining of almost same level. The tissue levels of radioactivity after 21 days repeated administration decreased gradually.
4. The percentages of unchanged Betaxolol and metabolites to radioactivity in plasma, tissues (liver, kidney and heart) and urine after repeated administration were almost same as those after a single administration.
5. Betaxolol had no effect on the hepatic drug-metabolizing enzyme system.

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The absorption, excretion and metabolism of Betaxolol were investigated in male and female dogs after oral or intravenous administration of ¹⁴C-Betaxolol.
1. After oral administration of ¹⁴C-Betaxolol(1mg/kg) to male and female dogs, the plasma levels of radioactivity reached the maxima at 2hr, and then decreased with half-lives of 1.7hr (T_1/2α) and 14.7hr (T_1/2β) in males, and 2.1hr (T_1/2α) and 13.2hr (T_1/2β) in females, respectively. Plasma levels of unchanged Betaxolol reached the maxima at 2hr after dosing, and then decreased rapidly with half-lives of 4.Ohr and 4.4hr in males and females, respectively.
2. After intravenous administration of ¹⁴C-Betaxolol(1mg/kg) to male dogs, the plasma levels of radioactivity decreased rapidly until 15min, and then increased gradually until 3hr after dosing. After that, the plasma levels of radioactivity decreased with half-lives of 3. Ohr and 12.2hr (T_1/2β). Plasma levels of unchanged Betaxolol decreased rapidly with half-lives of 1.8min (T_1/2α) and 3.8hr (T_1/2β).
3. After oral administration of ¹⁴C-Betaxolol, the radioactivity was readily and almost completely absorbed from the gastro-intestial tract. The systemic bioavailability was about 60%.
4. In both male and female dogs, approximately 95% of the administered radioactivity was excreted in urine (81-85%) and feces (11-14%) within 120hr after oral or intravenous administration of ¹⁴C-Betaxolol.
5. Major metabolic routes of Betaxolol in dogs were 0-dealkylation of cyclopropylmethoxyethyl moiety and N-dealkylation of isopropylaminopropoxy moiety.

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The absorption, distribution and excretion of KB-2796 were studied in male and female rats after single oral administration of [¹⁴C] KB-2796.
1. Maximum blood concentration of radioactivity appeared at 1hr after administration to male rats at a dose of 2mg/kg and the secondary peak occurred at 12hr after dosing. Thereafter blood concentration decreased with the terminal half-life of 42.9hr. The blood concentrations were increased proportionally to the administered doses ranging from 2mg/kg to 20 mg/kg. The blood concentrations in female rats decreased more slowly than that in male rats with a terminal half-life of 79.4hr.
2. Male rats excreted 67.4% of the dose in bile and 6.4% of the dose in urine within 48 hr after dosing and 5.7% of the dose remained in the carcass. The absorption rate from the intestinal tract was assumed to be about 80%. The radioactivity was mainly excreted in feces via bile and partly underwent enterohepatic circulation. The biliary excretion in female rats was lower than that in male rats and the radioactivity was slowly eliminated from the body.
3. Tissue concentrations of radioactivity were over 3 times higher than the plasma concentration except for the concentrations in the blood and eyeball at 6hr after administration to male rats. The high radioactivity was found in the lung, liver and fat, and disappeared slowly from tissues. Tissue concentrations in female rats were higher than those in male rats.
4. The plasma protein binding in vitro was independent of the concentration (0.04-1μg/ml), and was about 60% in rats and 80% in human. In vivo study, 69.5-82.0% of radioactivity was bound to protein of male rat plasma collected 1hr to 24hr after administration.

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Blood or plasma concentration, distribution, metabolism and excretion of ulinastatin were investigated in rats, mice and rabbits after single intravenous administration of ¹²⁵I-ulinastatin.
1. After administration of ¹²⁵I-ulinastatin to rats, mice and rabbits, blood or plasma levels of the radioactivity and that of the high molecular weight fraction decreased rapidly in biphasic manner. The half-lives of radioactivity in α and β phase were 4.2 ?? 9.5 min and 88 ?? 225 min, respectively. The half-lives of radioactivity of the high molecular weight fraction in α and β phase were 5.1 ?? 8.0 min and 32 ?? 80 min, respectively.
2. At 2.5 min after administration of ¹²⁵I-ulinastatin to male rats, high radioactivities were observed in the kidney, decreased rapidly like in case of the plasma.
3. Within 168hr after administration of ¹²⁵I-ulinastatin to rats, mice and rabbits, urinary and fecal excretion of radioactivity were 90.0 ?? 96.5% and 2.2 ?? 5.6% of the dose, respectively. Within 24hr after administration to male rats, biliary excretion of radioactivity was 2.9% of the dose.
4. At 1 and 10 min after administration of ¹²⁵I-ulinastatin to male rats, the radioactivity in the plasma was detected at the peak(67K peak) as a moiety with a molecular weight of ca. 67000 as same as that of ulinastatin determined by gel filtration chromatography. At 120 min after administration, the radioactivity in the plasma was detected at the peak (LMW peak) represented a compounds of a molecular weight less than 10000. Most of the radioactivity in the urine collected within 24hr after administration was detected at LMW peak on gel filtration chromatography, but the radioactivity was detected at 67K peak also.
5. At 168hr after administration of ¹²⁵I-ulinastatin to male rabbits, the radioactivity in the supernatant of centrifuged thyroid homogenate was detected at the peak with a molecular weight of ca. 670000 as same as that of thyroglobulin on the gel filtration high performance liquid chromatography.

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Glutathione S-transferases (GSTs) are one of the important enzymes in terms of not only drug metabolism but also physiological functions. The marked sex difference in GST activity has been found in rat liver cytosol, and such differences are suggested to be primarily due to the differences in the subunit composition of GSTs in both sexes. GSTs are widely distributed in mammalian species, and can be grouped into three distinct species-independent classes named alpha, mu and pi. The pi class GST 7-7 as a new mark er for preneoplasia is almost undetectable in normal rat liver. Normal dog liver cytosol has, however, possessed abundantly GST isozymes which are immunologically identical to GST 7-7. The present review also describes multiple forms of several animal species.

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