Novel derivatives of 3-[[[2-(3, 4-dimethoxyphenyl)ethyl]carbamoyl]methyl]aminobenzamide (1) were synthesized in order to improve the solubility and bioavailability of the parent compound (1). Biopharmaceutical characteristics and antiulcer activity of the synthesized compounds were evaluated in rats. Three derivatives showed substantial improvement in aqueous solubilities. The absorption was also improved as determined by in situ loop method. Each of these three derivatives was administered orally to rats. The compound (4) and N-sulfomethyl derivative (5) were found to be more active in preventing stressinduced gastric ulcerration than the parent compound (1). Serum concentrations were also measured for each of these derivatives, but no significant improvement in bioavailability compared with compound (1) was observed. These results may implicate that the compounds (4) and (5) do not act as the prodrug of compound (1).
In conclusion, although no useful prodrug has been found, the novel compounds (4) and (5), which show antiulcer activity were discovered. The utility of these compounds as antiulcer agents is currently under investigation.

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Pharmacokinetic studies of plasma levels of Flutamide, a pure antiandrogen agent for prostate cancer, were performed in rats after a single oral and intravenous administration at doses of 5 and 10 mg/kg, respectively.
1. Hydroxy-flutamide (OH-Flutamide) was a major metabolite in rat plasma after oral and intravenous administration of Flutamide.
2. Plasma concentration of Flutamide and OH-Flutamide reached C_max of 34.1 ng/ml (T_max: 0.5 hr) and 495.8 ng/ml (T_max: 2 hr) after a single oral administration of Flutamide at a dose of 5 mg/kg to male rats, and then decreased with half-lives of 0.45 and 3.8 hr, respectively. The C_max and AUC increased proportionally to the administration doses.
3. After an intravenous injection of Flutamide to rats, plasma levels of Flutamide and OH-Flutamide decreased with half-lives of 0.46 hr and 4.1 hr, respectively.

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Blood and plasma levels, tissue distribution and excretion of Flutamide, a pure antiandrogen agent for prostate cancer, were examined in rats after a single oral administration of ¹⁴C-Flutamide at a dose of 5 mg/kg.
1. The radioactivity in blood and plasma reached C_max of 2.46 and 2.09 μg/ml (Flutamide equivalent) at 2hr, respectively.
2. The radioactivity was well distributed in all tissues, especially in the kidney, fat, adrenal glands and the liver at 2 hr after oral administration. The radioactivities in these tissues were 2.8 ?? 4.8 times higher than that in plasma. The radioactivity in the most of tissues disappeared similarly as that in plasma.
3. The radioactivity was excreted within 120 hr into the urine, feces and the expired air at the rates of 70.2, 24.1 and 0.9% of the dose, respectively. The total recovery of radioactivity from the urine was 70.2% of dose, suggesting good gastro-intestinal absorption of Flutamide.

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Pharmacokinetic studies of Flutamide were performed in rats. Blood and plasma levels, tissue distribution and excretion of Flutamide were examined during and after the consecutive oral administration of ¹⁴C-Flutamide at a daily dose of 5 mg/kg for 21 days.
1. The blood levels of radioactivity at 24 hr after daily dosing increased with the number of dose, reaching the steady state on day 16.
2. The radioactivity was well distributed in all the tissues following the consecutive oral doses. The concentrations in the blood, small intestine, kidney, spleen, preputinal gland, stomach and the liver were 4.4 ?? 6.0 times higher than those after a single dosing, and that in the other tissues were 2.6 ?? 3.8 times higher. The radioactivity in most tissues after the final dosing was eliminated slowly from the tissues.
3. Excretion rates of radioactivity into urine and feces were 68.2 and 24.6% at 120 hr after the final dosing, respectively. These were almost constant duringthe consecutive oral doses. Residual radioactivity in rats was 0.6% of the total doses.

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The metabolism of Flutamide was examined after oral administration (5 mg/ kg) to male rats. Additionally the site of absorption, biliary excretion, enterohepatic-circulation and enzyme induction were studied.
1. After a single oral administration of ¹⁴C-Flutamide to bile-duct cannulated rats, the radioactivity was excreted into bile, urine and feces at the rate of 26.3, 65.3 and 1.1% of the dose, respectively. This finding suggested that Flutamide was well absorbed from intestinal tract and predominantly excreted to feces via bile.
2. After intraduodenal injection of the bile collected from other rats, which had been administered, 39.3% of injected radioactivity was excreted into bile and 44.5% into urine. This result suggested the presence of the enterohepatic circulation.
3. After the injection of ¹⁴C-Flutamide into various loops prepared from the gastro-intestinal tract of rats, radioactivity was well absorbed from the entireintestine and caecum.
4. After a single oral administration of ¹⁴C-Flutamide to rats, FLU-3 sulfate was formed to be the major metabolite in the urine, while OH-Flutamide glucuronide and M-1 were mainly found in the bile. The parent compound was also excreted in minor extents.
5. Consecutive administration of Flutamide did not affect the liver weight, microsomal cytochrome P-450 contents and drug-metabolizing activities in rat liver.

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The plasma level, distribution, metabolism and excretion of Edobacomab, a novel anti-endotoxin mouse IgM monoclonal antibody were investigated after intravenous administration of [³H]Edobacomab and unlabelled Edobacomab to experimental animals.
1. The radioactivity level in the plasma declined biexponentially after intravenous dose of the radiolabelled Edobacomab to male rats. Pharmacokinetic profile of radioactivity in rat plasma was similar to that from unlabelled Edbacomab. Plasma half lives in β phases were 11 ?? 15 hr in rat and monkey, and 21 ?? 23 hr in rabbit. The plasma levels showed dose proportionality in rat and rabbit, and the range of distribution volume was 28 ?? 48 ml/kg in these animals which is almost equal to the plasma volume.
2. The radioactivity was highest in plasma and distributed highly to reticuloendothelial tissues (eg. liver, spleen). Most of the radioactivity in plasma consisted of the unchanged drug, and small molecule metabolites were found in the spleen.
3. The cumulative urinary and fecal excretions of radioactivity were 95.7% and 0.9% of the dose, respectively, during 168 hr postdose. No unchanged drug was found in urine.

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The absorption, distribution, metabolism and excretion of the β₂-adrenoceptor agonist TA-2005 in rat, dog, and monkey were studied.
The extent of absorption calculated from the ratio of urinary excretion after oral (0.3 mg/ kg) and intravenous (0.1 mg/kg) administration of ¹⁴C-TA-2005 was 16 and 24% of the dose in male and female rats, respectively. In dogs, the absorption extent after oral administration (0.02 mg/kg) was above 60%, indicating a considerable species difference. The absorption extent from the ligated intestine of the rat was inhibited by the presence of bile. The C_max of plasma radioactivity after oral administration (1 mg/kg) in the rat was only 6.4 ng eq./ml at 15 min. Tissue levels of radioactivity were high in the digestive tract and liver and low in other organs and tissues. In male rats, the urinary and fecal excretion ratios of radioactivity within three days after oral administration were 3.2 and 90.7% of the dose, respectively, and those after intravenous administration were 20.3 and 75.7%, respectively. The ratios in female rats were similar to the respective ratios in male rats. In male dogs, the urinary and fecal excretion ratios during three days after oral administration (0.02 mg/kg) were 60.8 and 37.7%, respectively. In male monkeys, the urinary and fecal excretion ratios during seven days after oral administration (0.3 mg/kg) were 14.3 and 79.5%, respectively, and those after intravenous administration (0.1 mg/kg) were 60.0 and 34.4%, respectively. In rats, the ratios of biliary excretion within 24 hours after intraduodenal and intravenous administration were 55.2 and 81.5% respectively, indicating that the main excretion route in this species is the bile.

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Fluvastatin (FV) is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Absorption, distribution and excretion of the drug were investigated in rats after single administration of [¹⁴C]FV.
1. After oral administration of [¹⁴C]FV at doses of 0.25, 1, 5, 10 and 20 mg/ kg, the radioactivity in the blood reached the maximum concentration (C_max) between 1 and 2 hr, and declined with half-lives range of 7 ?? 11 hr. The values of both C_max and AUC increased in a dose-dependent manner. [¹⁴C]FV was absorbed mainly from the intestine, and the extent of absorption was estimated to be 61 ?? 84%.
2. Concentration of the unchanged FV in the plasma reached the maximum at 0.5 hr after oral administration of [¹⁴C]FV, and decreased with half-life of 3 ?? 4 hr. Bioavailability of the drug was about 46% at 1 mg/kg.
3. Distribution of the radioactivity to tissues was rapid and the maximum concentrations were attained within 2 hr after oral administration (1 mg/kg). Majority of the radioactivity was found in the liver and gastro-intestinal contents. At 24 hr, the levels of the radioactivity in the liver and intestinal contents were low, and those in another tissues were negligible.
4. Plasma protein binding of [¹⁴C]FV was over 97 ?? 99% in rat, dog and human. Binding ratio of [¹⁴C]FV to human serum albumin showed to be 94 ?? 97%. After oral administration of [¹⁴C]FV to rats, binding ratio of the radioactivity to plasma protein was 97 ?? 99%.
5. Excretion of the radioactivity in urine and feces within 144 hr after oral dosing was 4% and 95% of the dose, respectively. In bile duct-cannulated rat, biliary excretion was 83%, and the 58% of the radioactivity excreted into bile was reabsorbed.
6. No sex difference was observed in the pharmacokinetic parameters.

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Transfer of radioactivity to the fetus and milk were studied in pregnant and lactating rats after single oral administration of [¹⁴C]Fluvastatin (FV) at the dose of 1 mg/kg.
1. The maximum levels (C_max) of radioactivity in the fetuses on days 12 and 19 of gestation were observed at 6hr after the administration of [¹⁴C]FV and accounted for 5 % and 30% of the C_max in the maternal plasma, respectively. The amount of radioactivity transferred to a fetus was 0.01 ?? 0.3% of the dose.
2. On day 19 of gestation, the radioactive levels in the fetal liver and gastro-intestinal tracts were higher than those in another fetal tissues and those were the same levels in the maternal plasma at 6 hr after the administration of [¹⁴C]FV. Elimination of the radioactivity from the fetal tissue was slower than that from maternal plasma.
3. The radioactivity in the milk reached C_max at 8 hr after the administration of [¹⁴C]FV and the value was about 4 times higher than that in plasma. Elimination half-life (t_1/2) of the radioactivity in the milk was similar to that in the plasma.
Absorption, distribution and excretion of [¹⁴C]FV were investigated in male rats after 21-day consecutive daily oral administration at the dose of 1 mg/kg.
1. Steady-state in the blood levels of radioactivity was attained within 3 ?? 4 days.
2. C_max after the final dose was 1.8 times higher than that after 1st dose, but the time to C_max. (t_max), t_1/2 and AUC were not changed.
3. After the final administration, the radioactivity was mainly observed in the liver and gastro-intestinal tracts. The distribution pattern was similar to that observed after the single administration. No accumulation of the drug and its metabolites in the tissues after the consecutive oral administration of [¹⁴C]FV was observed.
4. Cumulative excretion of the radioactivity in urine, feces and expired air accounted for 2.2%, 94.7%, and 0.1% of the total dose, respectively, within 120 hr after the final administration.

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The pharmacokinetics of sotalol enantiomers in rats, after a single (10, 100, 300 mg/kg) and repeated (30 mg/kg/day, once daily for 7 days) oral administration of sotalol hydrochloride, were studied using stereo-selective HPLC method. Two different blood-collecting schemes were compared.
1. After a single oral administration, d- and l-sotalol showed linear pharmacokinetics in rats.
2. In the repeated administration study, the pharmacokinetics of d- and l-sotalol after first and seventh administration were not different from each other, and no accumulation was observed.
3. No enantiomeric difference was observed in the pharmacokinetics after a single and repeated administration of sotalol hydrochloride.
4. The mean urinary excretion of sotalol enantiomers within 48 hr after a single administration were about 70% for both d- and l-sotalol. The majority of the d- and l-sotalol was excreted within 24 hr.
5. Pharmacokinetics of the enantiomers were studied using two different blood-collecting protocols, (1) blood sampling from the same rats sequentially, (2) blood sampling from different rats for each time point. No significant difference on the pharmacokinetics of d- and l-sotalol was observed for both method.
6. Mean serum protein binding of d- and l-sotalol was low and accounted for approximately 9 %. No marked difference was observed between sotalol enantiomers, among species and concentrations.

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Renal handling of drugs is a complex phenomenon involving glomerular filtration, tubular secretion and tubular reabsorption. Tubular secretion of organic cations and anions is viewed as a means of eliminating exogenous, toxic compounds such as drugs from the body. The sequence of movement of organic ions is transport across basolateral membrane, diffusion in the cells, followed by efflux from the cell across brush-border membrane. The luminal, intracellular and peritubular compartments are separated by two distinct membranes, luminal brush-border and contraluminal basolateral membrane. To characterize the specific membrane events underlying the transcellular transport of organic ions, we have used brush-border and basolateral membrane vesicles isolated from renal cortex. In addition, we have established the in vitro model system to study the secretory process of organic ions in intact cells using cultured renal cells.
This article concerns the transport mechanisms of tetraethylammonium (organic cation) in renal brush-border and basolateral membranes, and characteristics of transcellular transport of p-aminohippurate (organic anion) in OK cells, an established cell line derived from the American opossum kidney. The studies with isolated plasma membrane vesicles and cultured renal cells would provide new insights into our understanding of renal tubular transport mechanisms of drugs.

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This review describes our recent investigation on the pharmacokinetic analysis of liposome disposition, especially hepatic uptake of liposomes. We have examined the saturable uptake processes of liposomes by the liver and postulated a new kinetic model “Manpuku Model (Satiated Model)” which explains AUC-dependent saturation kinetics of liposome uptake by the liver. This model assumes that the hepatic uptake clearance (CLh) is described by the maximum hepatic uptake clearance (CLh, max), maximum hepatic uptake (X_max) and the hepatic uptake (X) as CLh=CLh, max (1-X/X_max). This model explains the saturation kinetics of hepatic uptake of liposomes well and can be applicable to characterize the saturation kinetics of other kinds of liposome uptake.
The mechanism of hepatic uptake of liposomes was investigated using isolated perfused liver and hepatic uptake of liposomes was shown to be enhanced by preincubation with serum. This opsonic activity was shown to be mediated via complement receptor mediated phagocytosis. The activation of complement system dependended on the size of liposomes. There are two kinds of uptake pathways, one via size dependent, complement receptor mediated pathway, the other is size independent, nonspecific pathway.
The intracellular disposition of liposomes was further examined using ¹²⁵I-BSA as a degradable, aqueous phase marker in the isolated peritoneal macrophages. The intracellular degradation of liposomes was shown to be biphasic. The degradation process of liposomes was also examined in intact liver and biphasic pattern was confirmed. These results indicate heterogeneous intracellular disposition (both transport and degradation) of liposomes.
The rational strategies for the drug delivery system using liposomes will be developed based on both quantitative evaluation of liposome movement in blood circulation, hepatic uptake and intracellular disposition and clarification of the mechanisms of liposome uptake and intracellular disposition of liposomes.

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Interethnic differences for the frequencies of poor metabolizers (PMs) of sparteine/metoprolol and mephenytoin type of oxidation were studied in the Japanese, Korean, Indonesian and Chinese populations. The frequencies of PMs for the α-hydroxylation of metoprolol in Japanese, Korean, Indonesian and Chinese populations (0-0.7%) were ten-times less than that of Caucasians (7%). On the other hand, the frequencies of PMs for the 4'-hydroxylation of mephenytoin were much higher in Japanese (20%), Korean (13%), Indonesian (15%) and Chinese (18%) populations when compared with the Caucasian populations (3%). These differences of the incidence of PMs of metoprolol and mephenytoin oxidation polymorphism between Oriental and Caucasian populations suggest that drugs which are established for their safety in European or North American countries cannot always be introduced safely to Oriental countries and vice versa. Since mephenytoin type of drug oxidation is particularly important for assessing drug safety in Japanese population, we developed a simple assay of S-mephenytoin 4'-hydroxylation activities in human liver microsomes. Using this assay method, we found that 5-hydroxylation of omeprazole is mainly catalyzed by CYP2C19. We confirmed the finding obtained from the in vitro study using human liver microsomes, by in vivo panel study, which showed that mean AUC of omeprazole is significantly higher in PMs than extensive metabolizers of mphenytoin. The findings suggest that in vitro method using human liver microsomes is useful to assess an involvement of CYP2C19, an isoform of cytochrome P450 showing marked genetic polymorphism in Japanese population, in the metabolism of drugs under development.

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