The absorption, distribution, metabolism and excretion of ¹⁴C-dilevalol (Sch-19927) were studied following a single oral or intravenous administration to rats.
1. Plasma levels of radioactivity reached a maximal concentration 1 hr after oral administration of 30 mg/kg to male and female rats corresponding to 6.30 and 7.84 μg equivalents of Sch-19927/ml, and then declined with half-lives of 2.59 and 3.22 hr, respectively. A similar profile of plasma radioactivity was obtained at the 10 mg/kg oral dose.
In the in situ experiment, about 30 % of the injected radioactivity was absorbed from the duodenum, jejunum, ileum and rectum but not from the stomach. Most of the radioactivity in the plasma was found to be Sch-19927 glucuronide (M3), with unchanged Sch-19927 accounting for only 1-2 %. The plasma protein binding in vitro was about 60 % and that in vivo was 23 % measured in the plasma samples collected 1 to 6 hr after administration.
After intravenous administration at 10 mg/kg, the half-life of radioactivity in the plasma was 1.2 hr (2 min-4 hr) in both male and female rats. A relatively high proportion of unchanged Sch-19927 was observed in the plasma.
2. The kidney, liver and lung contained high concentrations of radioactivity after oral administration at 30 mg/kg. The radioactivity was cleared from tissues, except the testis, as found with plasma. Though the level was low, the radioactivity in the testis disappeared more slowly than from other tissues. Qualitatively similar tissue distribution was observed by whole-body autoradiography.
3. Male and female rats excreted about 50 % of radioactivity in urine and feces until 120 hr after oral administration at 30 mg/kg. Excretion of radioactivity in bile was 42 % of the dose in males and 57 % in females, with 15 % of the dose entering the enterohepatic circulation. About 80 % of the radioactivity in urine and 40 % in bile were excreted as M3.

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The absorption, distribution, metabolism and excretion of ¹⁴C-dilevalol (Sch-19927) were studied following a 10-day period of daily oral administration to male rats at 30 mg/kg/day.
1. The plasma level of radioactivity at 24 hr after every dosing was below the detection limit until the 5 th dosing and did not increase significantly after the 7 th dosing. The maximal concentration was observed 1 hr after the last dose (5.73 μg equivalent of Sch-19927/ml) and declined with a half-life of 2.53 hr until 8 hr. Most of the radioactivity in the plasma was identified as Sch-19927 glucuronide (M 3).
2. The tissue level of radioactivity reached a plateau by the 5 th dosing. It disappeared more slowly than that after a single dose but accumulation in all tissues except for the testis was low. The testis showed a low accumulation and a residue of radioactivity was due to the unchanged Sch-19927.
3. Repeated administration did not change the excretion profile, and the amount of metabolites excreted during 24-hr to urine after the last dose was similar to that found after a single dose; 77% of the urinary radioactivity was accounted for M 3, with a little of unchanged Sch-19927 and other metabolites being detected.

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Transfer of ¹⁴C-dilevalol (Sch-19927) into the fetus and milk were studied following oral administration to pregnant or lactating rats at the dose level of 30 mg/kg.
1. On day 12 of gestation, the radioactivity in the fetus was lower than that in the maternal plasma. On day 19 of gestation, high radioactivity was observed in the yolk sac and amnion. The radioactivity in the fetus on day 19 was higher than that on day 12 of gestation. Radioactivity levels in the fetal gut, liver, kidney and lung, were considerably high, but less than a half of that in the maternal plasma. The distribution and disappearance of radioactivity in pregnant rats were similar to those in non-pregnant rats.
2. The concentrations of radioactivity in the milk were 1/4-1/2 of that in the maternal plasma.

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The absorption, metabolism and excretion of ¹⁴C-dilevalol (Sch-19927) were studied following a single or a 10 day period of daily oral administration to dogs at 30 mg/kg.
1. The plasma levels of radioactivity reached a peak level (15.22 μg equivalent of Sch-19927/ml) 2 hr after a single dosing and declined with a half-life of 4.43 hr until 8 hr. Two hours after dosing, 26 % of the radioactivity in the plasma was due to unchanged Sch-19927, 40 % was MD₁ and 25 % was M₃.
The in vitro plasma protein binding experiments showed that Sch-19927 was bound in more than 90 % at 0.1 and 1 μg/ml but about 60 % at 10 μg/ml concentrations in dog plasma.
The in vivo binding was 35 and 69 % determined in the plasma samples collected 2 and 24 hr ather administration, respectively.
2. Excretion of radioactivity was 66 % of the dose in urine and 32 % in feces by 120 hr after single dosing. Of the urinary radioactivity, 6 % was unchanged Sch-19927, 52 % MD₁ and 18 % M₃. MD₁ and M₃ were assumed to be alcoholic and phenolic glucuronides of Sch-19927, respectively.
3. During repeated administration, the plasma level at 24 hr after every dosing showed no marked change. It reached a peak level (16.99 μg equivalent of Sch-19927/ml) at 1.5 hr after the last dose and declined more slowly than after single dosing witn a half-life of 7.12 hr until 8 hr. Two hours after repeated dosing, 32 % of the radioactivity in the plasma existed as unchanged Sch-19927, 28 % as MD₁ and 17 % as M₃.
4. Within 120 hr after the last dose, the excretion radioactivity in urine was 65 % of the dose and that in the feces was 31 % of the dose. This urine had proportions of unchanged Sch-19927 and metabolites similar to those found after single administration.

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Absorption, distribution, metabolism and excretion of a new morpholine derivative Y-8894 were investigated in mice, rats, guinea pigs and rabbits by administration of ¹⁴C labeled compound (¹⁴C-Y-8894) at a dose of 30 mg/kg.
Urinary and fecal recoveries of radioactivity (¹⁴C) within 4 days following oral administration were 52.2 % and 46.8 % in mice, 24.3 % and 72.5 % in rats, 73.4 % and 22.5 % in guinea pigs, and 64.8 % and 26.0 % in rabbits, respectively. About 93 % of the given ¹⁴C was recovered in the rat bile within 24 hours after oral administration.
Maximum blood levels of ¹⁴C were obtained within 1 hour after oral administration in all species examined, with all initial biological half-lives (T 1/2) in the range of 1.0 ?? 1.8 hours. Terminal T1/2s were 21.2 ?? 25.8 hours for all species except the guinea pigs. The blood levels in guinea pigs were not detectable 24 hours after oral administration.
The highest levels of ¹⁴C were observed in the liver, kidney and lung of mice, and in the liver of rats 0.5 hours after oral administration, and relatively high levels in the lung and kidney of rats, in the adrenal, pancreas, salivary gland and spleen of both mice and rats. Brain levels in both mice and rats were twice of that in the blood. Twenty-four hours after administration significant amount of ¹⁴C were detected only in the liver and kidney.
Protein bindings of ¹⁴C in the serum were in the range of 63 ?? 83 % for all species.
Major metabolites of Y-8894 in urine of mice were similar to those in urine and bile of rats, but somewhat different from those in urine of guinea pigs and rabbits.

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The biliary and urinary metabolites of a new morpholine derivative Y-8894 were investigated in rats and rabbits after oral administration of Y-8894.
Unchanged Y-8894 and eight metabolites were purified and isolated using an Amberlite XAD-2 resin column, preparative thin-layer chromatography and high pressure liquid chromatography. The structures of these metabolites were identified by their mass, infrared and nuclear magnetic resonance spectra.
The major metabolic pathways of Y-8894 in rats and rabbits are considered to be as follows: a) hydroxylation of phenyl ring and successively oxidation of morpholine ring, b) hydroxylation of thiophene and N atom of morpholine ring, and these hydroxylated derivatives were excreted in urine or bile mainly as glucuronides, c) opening of thiophene ring and sulphoconjugation at N atom of morpholine ring.

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The distribution of Biscoclaurine Alkaloid, Cepharanthine (Ceph) in rat after iv administration was examined using autoradiography and immunohistochemical techniques. Ceph distribution was high in the spleen while in the endocrine organs, liver, kidney, lung and gastrointestinal tract, the distribution was of moderate degree. Furthermore, if it was in a lower concentration, Ceph was located in heart, skeletal muscle, bone marrow and lymphoid tissues. The amount of Ceph in the liver was increased gradually and it was present not only in the cytoplasm but also in the nucleus of liver cells. During the early phase, Ceph was mainly observed in splenic red pulp, however in the late phase it was found both in red and white splenic pulps as well. It confirmed that Ceph was excreted mainly from gastrointestinal tract and partly with the bile, urine and expired air. Further, Ceph was frequently distributed in matured T cells in thymus.
It concluded that Ceph was able to distribute widely in whole body and was able to penetrate into the nucleus and cytoplasm of many cell types. Further, it seemed that Ceph played an important role in huge area of rat body.

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A Cell is a basic unit of the living body. It is separated from extracellular space by the cell membrane, which consists of lipid bilayers. When a drug is administered to the body, it contacts inevitably with the cell membranes. Therefore, its fate in the body must be strongly influenced by its liopphilicity which determines its degree of penetrability through the cell membranes.
For this reason, it is necessary for us to know the boundary between lipophilicity and hydrophilicity of drugs from the pharmacokinetic point of view. In order to clarify this boundary, I tried to analyze the relationship between partition coefficients and several pharmacokinetic parameters of various drugs and found some regularities, represented as below;
1) Drugs (log P^*>-2) are lipophilic from the viewpoint of volume of distribution.
2) Drugs (log P^*<-1) are hydrophilic, whereas, drugs (log P^*>0) are lipohilic from the viewpoint of the rate of excretion unchanged in urine.

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β-Adrenoceptor blocking drugs (β-blockers) are widely used in the medical management of cardiovascular diseases. β-Blockers have two optical isomers and mainly the l-isomer has β-blocking activity, but many of the drugs are used as racemate for the clinical therapy. Studies on pharmacodynamic and pharmacokinetic relationships of β-blockers are important for clinical pharmacology. Because of low effective plasma concentrations (15-58 ng/ml), attempts have been made to develop sensitive, specific and simple immunological methods for the determination of β-blockers in plasma. Development of various types of immunoassay has been reported for dl-propranolol (PPL), l-PPL, acebutolol, diacetolol, oxprenolol, bunitrolol and befunolol. Each of these immunoassays appears to have sufficient sensitivity for the determination of plasma drug concentrations. Stereospecific radioimmunoassay for PPL isomers has revealed excellent correlation of β-blocking activity with plasma dl- and l-PPL concentrations, and longer half-life (T_1/2β) for l-PPL in rabbits, but no difference in T_1/2β between the isomers after single oral dose of dl-PPL in hyperthyroid patients. Although immunoassay for β-blocking drugs may sometimes encounter with problems of specificity, it has certainly advantages of sensitivity, simplicity of operation and stereospecificity.

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