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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我々は，ラットに ¹⁴C-Flutamide を単回経口投与したときの胆汁排泄，腸管循環，消化管吸収，ならびに代謝および酵素誘導について検討した．
1．ラットに ¹⁴C-Flutamide を単回経口投与したとき，48時間後には胆汁に26.3%，尿に65.3%および糞に1.1%の排泄が認められ，主排泄経路は尿であった．
2．ラットに ¹⁴C-Flutamide を単回経口投与し，24時間までに排泄された胆汁を別のラットの十二指腸内に投与した時，投与された放射能の 39.3% が再び胆汁中に，また，44.5% が尿中に排泄されたことから，腸管循環が認められた．
3．消化管を胃，十二指腸，小腸(上部，中部，下部)，盲腸に分けて結紮し，¹⁴C-Flutamideを注入したときの吸収率を調べた．Flutamide は小腸全域から盲腸にかけて良く吸収され，速やかに門脈血へ移行すると考えられた．また，胃からの吸収は，分布実験8)において，残留が認められないことから，比較的緩やかなものと推察された．4、尿中の主代謝物は FLU-3 の硫酸抱合体であった．
5．胆汁中の主代謝物は OH-Flutamide のグルクロン酸抱合体および代謝物 M-1 であった．
6．Flutamide を反復投与し，酵素誘導について調べたところ，対照群と有意差は認められず，肝薬物代謝酵素への影響は認められなかった．

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実験動物を用いてエドバコマブの単回静脈内投与時の血中動態，体内分布，代謝および排泄を検討した．
1．ラットに静脈内投与した時，血漿中濃度は用量とともに増加した．また，[³H]エドバコマプを静脈内投与した時の血中動態はエドバコマブ投与時と同様であり，血漿中濃度は二相性に消失したが性差は認められなかった．サルにエドバコマブを点滴静脈内投与した時の消失半減期はラットとほぼ同じであり，ウサギではT_1/2βはやや長く種差が認められた．いずれの動物においても，Vdは28～48ml/kgと小さくほぼ血漿量に相当し，エドバコマブは主として血液中に分布することが示された．2．[³H]エドバコマブを静脈内投与した時のラットの組織内放射能濃度は脾臓，肝臓などの細網内皮系組織で比較的高かったがいずれも血漿中濃度より低く，組織移行性が低いことが示された．この成績は，全身オートラジオグラムの成績とほぼ一致した．胸管リンパ液への移行も認められ，リンパ系の体内動態への関与が示唆された．
3．ラットに[³H]エドバコマブ静脈内投与した時，血漿中放射能の95%以上がTCA不溶性画分にあり，ゲル濾過クロマトグラフィーにおいても血漿中放射能の90%以上が未変化の[³H]エドバコマブであることが示された．脾臓ホモジネート上清中の放射能はそのほとんどが低分子代謝物であり，脾臓を初めとする細網内皮系組織が本薬の除去機構および代謝に強くかかわっていることが示唆された．
4．[³H]エドバコマブは投与後168時間までに投与放射能の約97%(尿96%，糞1%)が排泄され，尿中放射能はすべてTCA可溶性画分に存在し，Lipid A 結合性は認められなかった．

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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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インドール環に[¹⁴C]標識したFVを用い，雌雄ラットに単回経口または静脈内投与後の吸収，分布および排泄について検討し，以下の結果を得た．
1．[¹⁴C]FVを経口投与した場合，主として十二指腸，空腸等の小腸上部より吸収されて血中へ移行することが示された．雄性ラットに0.25，1，5，10 および 20mg/kg 経口投与後の全血中放射能濃度は，いずれの用量においても投与1～2時間後に C_max に到達し，その後7～11時間の半減期で消失した．C_max および AUC は用量依存的に増大した。本薬の吸収率は61～84%と推定された．
2．1または 20mg/kg 経口投与後の血漿中の未変化体は，いずれの用量ともに投与後 0.5時間で C_max を示し，3～4時間の半減期で消失した．本薬のバイオアベイラビリティは 1mg/kg 投与時で46%であった．
3．経口投与後の各組織内放射能濃度は，投与後2時間以内に最高濃度に達した．放射能は肝臓，消化管，次いで腎臓に高濃度に分布し，脳，精巣への移行は低かった．投与後24時間では，下部消化管内容物および肝臓にのみ放射能が検出された．
4．FVの血漿蛋白結合率はラット，イヌおよびヒトのいずれの種においても97～99%であった．また，HSAへの結合率は94～97%であった．[¹⁴C]FVを経口投与後の放射能の血漿蛋白結合率は97～99%であり，血球移行率は2～31%であった．
5．経口投与後144時間までに投与量の 3.72% の放射能が尿中に，95.36% が糞中に排泄され，呼気中への排泄は認められなかった．胆管カニューレを施したラットにおける胆汁，尿中への排泄率は，投与後48時間でそれぞれ投与量の 82.7%，1.05% であった．また，胆汁中に排泄されたもののうち，約58% が腸肝循環することが示された．
6．雌性ラットに経口投与後の尿，糞および呼気中排泄率，全血中放射能濃度推移ならびに薬物動態パラメータは雄の場合とほぼ同等であり，体内動態に性差は認められなかった．

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代謝的に安定なインドール環に[¹⁴C]標識したFVを用い，ラットに 1mg/kg で単回経口投与後の胎児および乳汁移行性について検討した．また，[¹⁴C]FVを 1mg/kg/day で21日間反復投与した時の血中濃度，分布および排泄について併せて検討を加えた．
1．[¹⁴C]FVを妊娠12日目および19日目のラットに経口投与後の胎児中の放射能は，投与後6時間で最高値を示し，母獣全血のCm砥のそれぞれ5%および30%を占めたことから，胎児への放射能の移行は妊娠後期に高まる傾向が認められた．
2．胎児の各臓器への放射能の分布をみると，主として肝臓および消化管で高く，投与後6時間で最高値を示し，同じ時点の母獣全血とほぼ同等であった．投与後24時間では，消化管内の放射能は母獣全血よりも高値を示し，胎児からの放射能の消失は母獣に比べやや緩慢であった．
3．[¹⁴C]FVを投与後の妊娠12日目の母獣の臓器・組織内放射能濃度は，非妊娠ラットにおける結果とほぼ同等であった．妊娠19日目のの母獣における放射能の分布は，C_max 付近で一過性に各臓器・組織内濃度は高まるものの，それ以後の消失および分布パターンは非妊娠および妊娠中期とほぼ同じであった．
4．[¹⁴C]FVを分娩後14日目の哺育中のラットに経口投与後の乳汁中放射能のほとんどは未変化体であり，投与後8時間で最高値に到達し，血漿の C_max の約4倍を示したが，血漿とほぼ平行して消失した．
5．[¹⁴C]FVを 1mg/kg で1日1回，21日間反復経口投与した時の全血中放射能濃度および尿，糞中への排泄率は3～4日目以後ほぼ定常状態に到達した．
6．21回投与後の全血の C_max は初回投与時に比べ1.8倍に増大したものの，t_max，t_1/2 および AUC に差は認められなかった．
7．定常状態における放射能の各臓器・組織内への分布パターンは初回投与時とほぼ同様であり，特定の組織への残留は認められなかった．
8．反復投与後120時間までの尿，糞および呼気中排泄率は，それぞれ総投与量のそれぞれ 2.2%，94.7%，0.1% であり，単回投与時とほぼ同等であった．

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塩酸 sotalol をラットに 10，100，300mg/kg 単回投与および 30mg/kg/day を1日1回7日間反復投与したときの，光学異性体の体内動態を光学分割定量法を用いて試験した．また，これらの試験を2種の異なる採血方法を用いて比較検討した．
1)塩酸 sotalol をラットに単回経口投与したとき，d-および l-sotalol はともに線形性の体内動態を示した．
2)反復投与における初回投与後と7回投与後の d- および l-sotalol の体内動態に変化は認められず，蓄積性のないことも確認された．
3)単回および反復投与において，d- および l-sotalol の体内動態に差は認められなかった．
4)単回投与したときの48時間までの尿中排泄率は d-体，l-体いずれも平均約70%であり，その大部分は24時間以内に排泄された．
5)Sotalol のラットにおける体内動態を，(1)同一動物から経時的に採血する方法と，(2)採血点ごとに異なる動物を使用し，多量の血液を採取する方法の2種類の試験方法で検討した結果，両試験法で得られた結果に顕著な差はみられなかった．
6)ヒト，イヌおよびラットの in vitro 血清蛋白結合率を測定した結果，d- 体および l-体の蛋白結合率は，いずれも平均約 9% と低く，光学異性体間に差はなく，種差および濃度による変化も認められなかった．

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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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