新規肝機能改善薬として開発されたTA-510の体内動態を明らかにする目的で，14C-TA-510を雄性ラットおよび雄性イヌに単回経口(30mg/kg)および単回静脈内(3mg/kg)投与した時の血中濃度推移，分布および排泄について検討した．1．14C-TA-510をラットおよびイヌに経口あるいは静脈内投与した時の尿中放射能排泄率の比から算出されたTA-510の消化管吸収率は，それぞれ約80%および100%であった．2．経口投与時において，ラット血漿中未変化体のCmaxおよびAUCはイヌに比べてそれぞれ約50倍および80倍低い値を示した．ラット血漿中の総放射能濃度のAUCに対する未変化体濃度のAUCの比率は僅か2%と少なく，TA-510は雄性ラットにおいて初回通過代謝を受けることが示唆された．3．ラット経口投与時において，消化管以外の多くの組織中の放射能は投与後6時間で最も高く分布し，血液より高濃度の放射能が標的臓器である肝臓の他に腎臓にも認められた．また，血液と同程度の放射能が肺と皮膚に認められた．脳，脾臓および精巣をはじめとした他の組織への放射能の分布は極めて少なかった．その後，組織中放射能は経時的に減少し，投与後72時間では消化管内容物と肝臓に僅かに認められたのみであった．4．ラットに経口投与後の72時間までに投与した放射能の27.5%および68.9%が尿および糞中に排泄された．また，ラットに経口投与後の48時間までの胆汁および尿中の累積放射能排泄率はそれぞれ72.2%および5.5%であった．体外に排泄された胆汁を再び十二指腸内に投与した際に，投与放射能の35.9%が吸収された．一方，イヌにおいて経口投与後72時間までの尿および糞中に回収された放射能は，それぞれ51.4%および44.7%であった．

The metabolites of TA-510, a novel hepatic agent, were investigated by HPLC and LC/MS/MS after oral administration of 14C-TA-510 (30 mg/kg) to rats and dogs or TA-510 (200 mg) to human. The presence of conjugated metabolites was confirmed by enzymatic hydrolyses. 1. Major radioactive components in the urine of rats and dogs and in the bile of rats were the glucuronides of O-demethylated metabolites which consisted of M2 (3'-O-demethylated form), M3 (4'-Odemethylated form), and M4 (3',4'-di-O-demethylated form). The unchanged TA-510 was found in trace amount, accounting for 0.25% and 1.38% of the administered dose in the urine of rats and dogs, respective ly. 2. Within 24 hr after administration to rats, in urine 4.89% and 4.18% of the dose were excreted into the urine as M3-glucuronide and M4-glucuronide, and 29.15% and 4.82% of the dose were excreted into the bile as M3-glucuronide and M2-glucuronide, respectively. In dog urine, main metabolite was identified as M3-glucuronide, 18.22% of the dose, and the other metabolites accounted for less than 2% of the dose. 3. Within 24 hr after oral administration of TA-510 to human, the unchanged TA-510 was hardly detect ed in the urine (0.04% of the dose), and three kinds of glucuronides were found to be the main metabolites. The enzymatic hydrolyses of the human urine produced the aglucones M1 (4-ketone reduced form), M5 (4'-O-demethylated form of M1) and M3, which accounted for 7.73%, 11.11% and 17.02% of the dose, respectively. 4. The metabolites of TA-510 in human urine were analyzed using chiral column because TA-510 was administered as a racemate. There was a large difference in the enantiomer ratios [5S, 6R, 7S] / [5R, 6S, 7R] among the metabolites, 4.22-10.41 as M1, 0.99-2.31 as M3 and 0.18-0.34 as M5, suggesting that TA-510 racemate might be metabolized enantioselectively.

CNS Drug ReviewsVolume 4, Issue 1 p. 25-41 Free Access Taltirelin Hydrate (TA-0910): An Orally Active Thyrotropin-Releasing Hormone Mimetic Agent with Multiple Actions Kiyoshi Kinoshita, Corresponding Author Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama 335-8505, JapanAddress correspondence and reprint requests to Dr. K. Kinoshita, Pharmaceutical Development Res. Lab., Tanabe Seiyaku Co., LTD., Kawagishi 2-2-50, Toda-shi, Saitama 335-8505, Japan. Fax: (81)48-433-8161.Search for more papers by this authorMichio Yamamura, Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama 335-8505, JapanSearch for more papers by this authorJuko Sugihara, Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama 335-8505, JapanSearch for more papers by this authorMamoru Suzuki, Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama 335-8505, JapanSearch for more papers by this authorYuzo Matsuoka, Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama 335-8505, JapanSearch for more papers by this author Kiyoshi Kinoshita, Corresponding Author Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama 335-8505, JapanAddress correspondence and reprint requests to Dr. K. Kinoshita, Pharmaceutical Development Res. Lab., Tanabe Seiyaku Co., LTD., Kawagishi 2-2-50, Toda-shi, Saitama 335-8505, Japan. Fax: (81)48-433-8161.Search for more papers by this authorMichio Yamamura, Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama 335-8505, JapanSearch for more papers by this authorJuko Sugihara, Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama 335-8505, JapanSearch for more papers by this authorMamoru Suzuki, Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama 335-8505, JapanSearch for more papers by this authorYuzo Matsuoka, Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama 335-8505, JapanSearch for more papers by this author First published: 07 June 2006 https://doi.org/10.1111/j.1527-3458.1998.tb00039.xCitations: 22AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Citing Literature Volume4, Issue1March 1998Pages 25-41 ReferencesRelatedInformation

After the intravenous administration of 14C-D-aspartic acid (Asp) into Sprague-Dawley rats (male, 7-week-old), the distribution and elimination of radioactivity was investigated by the whole body autoradiography. High radioactivities were detected in pineal gland, pituitary gland and salivary gland at 30min after administration. The other tissues detected were liver, lung, adrenal gland, pancreas and spleen where D- Asp was reported to occur naturally. After 24hr, the radioactivities were still detected at high levels in the pineal, pituitary and salivary glands. The data suggested the natural occurrence of D-Asp in salivary gland. After careful examination utilizing fluorescent derivatization and chiral separation by high-performance liquid chromatography, the presence of D-Asp was, for the first time, demonstrated in salivary gland in situ, the concentration of which was 7.85±1.0nmol/g. The administration of 14C-L-Asp was also carried out. The data suggested that D-Asp in the circulating blood is one of the sources of the tissue D-Asp.

The absorption, distribution, excretion and metabolism were investigated after a single oral (3 mg/kg) or intravenous (1 mg/kg) administration of 14C-taltirelin to male rats and dogs. 1. The extent of absorption calculated from the ratio of urinary excretion after or al and intravenous administration of 14C-taltirelin was 9 and 21% of the dose in rats and dogs. The intestinal absorption ratio in non-fasted rats decreased by 38% compared with that in fasted rats. 2. After oral administration to rats, the plasma level of radioactivity reached the maximum level of 157 ng eq./ml at 1 hr after dosing and then decreased with a half-life of 119 min. After oral administration to dogs, the plasma level of radioactivity reached the maximum level of 508 ng eq./ml at 1.5 hr and then decreased with a half-life of 146 min. The values of bioavailability in rats and dogs were 3.9 and 18.5%, respectively. 3. The ratios of plasma protein binding of radioactive substances in rats and dogs were below 12% both under the in vivo and in vitro conditions. 4. Radioactivity levels afte r oral administration to rats reached a peak at 30 min to 3 hr in most tissues and were high in the liver, kidney, spleen, lung, blood and skin, except for gastrointestinal tract. But at 24 hr radioactivity levels in these tissues decreased remarkably. Radioactivity level in the brain, a target organ of pharmacological effect, was low and decreased slowly. 5. In both rats and dogs, most of the dose wa s excreted within 48 hr after dosing and the absorbed 14C-taltirelin was excreted mainly in urine. 6. Radioactivity excreted in bile within 24 hr was 1.7 and 5.7% of the dose after oral and intravenous administration to rats, respectively. 7. Two metabolites, (−)-N-[(S)-hexahydro-1-methyl-2, 6-dioxo-4-pyrimidinyl carbonyl]-L-histidyl-L-proline (“Acid”) and (S)-hexahydro-1-methyl-2, 6-dioxo-4-pyrimidinecarboxylic acid (“MDOA”), together with unchanged taltirelin were detected in plasma and urine of both rats and dogs.

14C-taltirelinをラットに3mg/kg単回経口投与時の胎児移行性，乳汁中移行性および性差ならびに反復経口投与時の血液中濃度推移について検討した． 1．妊娠13日および19日のいずれにおいても，全胎児中放射能濃度は投与後3時間で最大値を示し，その時点における母獣血液中濃度のそれぞれ1/7および1/3であった．妊娠19日の胎児1匹当たりへの放射能移行量は投与後3時間で投与量の0.002%以下であった．胎児からの放射能の消失は母獣血液に比べ緩慢であった． 2．投与後1時間における血液および乳汁中放射能能度はそれぞれ11.0および8.9ng eq./gであった．乳汁中放射能の消失は血液中放射能の消失より遅く，投与後6時間以後の乳汁中放射能濃度は血液中濃度の約2倍で推移した． 3．血中放射能濃度のファーマコキネティックパラメータおよび尿中放射能排泄率に雌雄間で有意な差は認められなかった．24時間尿中における代謝物MDOAの占める割合は雄性ラットで18%，雌性ラットで約30%であり，代謝における量的な差が観察されたが質的な差はなかった． 4．1日1回15日間反復経口投与した時の最終回投与における血液中放射能濃度のCmax，t1/2，AUCinfは初回投与時に比べそれぞれ1.3，2.2および3.1倍に増加した．投与後1時間での血液中濃度は7日以内にほぼ定常状態に達した．

The transfer, distribution and degradation of taltirelin in the brain were investigated after oral (3 mg/kg) or intravenous (1 mg/kg) administration and injection into cisterna cerebellomedullaris (300 μg/kg) in rats. 1. Taltirelin was hardly degraded for 3 hr in blood, whereas TRH was degraded with a half-life of 5.4 min. Taltirelin and TRH were degraded by the brain homogenate with half-lives of 64.4 and 7.9 min, respectively, suggesting that taltirelin is 8 times more stable than TRH in the brain. In the cerebrospinal fluid taltirelin and TRH were equally stable for 3 hr. 2. Concentration of unchanged taltirelin in the brain decreased more slowly with a half-lives of 55.4 ?? 65.7 min than that in the blood (t1/2 : 23.1 min) after intravenous administration of taltirelin. After oral administration, the brain concentrations of unchanged taltirelin reached the maximum levels of 135 ?? 364 pg/g and then decreased slowly. The unchanged taltirelin was not detected in the brain at 6 hr after dosing. 3. After injection of 14C-taltirelin into cisterna cerebellomedullaris, the brain concentrations of radioactivity reached the maximum levels of 2.3 ?? 5.5 μg eq./g at 1 hr after injection and then decreased slowly. These results indicated that taltirelin was transferred from cerebrospinal fluid into the brain, in which taltirelin was retained for a long time. 4. After intravenous adm inistration of 14C-taltirelin or 3H-TRH, there is a difference in the brain distribution of radioactivity between taltirelin and TRH. Radioactive concentration in pituitary gland, which was target organ of hormonic effect, at 5 min after intravenous administration of 14C-taltirelin was 1/10 of that after dosing of 3H-TRH.

The colored substances excreted in bile or urine have bee investigated after adminstration of a high dose of SQ-504 to rats. A reddish-violet colored substance and a bluish-violet colored substance were dominant. Their chemical structures were not assigned because of their small quantity and instability. It was recognized that the colored substances were metabolites of SA-504 from the studies with 3H and 14C labelled SA-504 and the derivatives of SA-504.

The Penfluridol (PFL) is a potent and long-acting neuroleptic belonging to the diphenylbutyl piperidine series. The purpose of the present study is to investigate a correlation between the brain concentration of unchanged 3H-PFL and its neuroleptic activity in the methamphetamine-antagonism test. The experimental animal comprised adult male Wistar rats weighing about 200 g. All the rats were administered 3H-PFL orally and killed at appropriate times after administration. After killing blood samples were collected and the brain and liver were excised. The blood was extracted with 4 volumes of ethanol. The brain and the liver were homogenized in 9 volumes of ethanol. The amount of 3H-PFL in the ethanol extract was determined by thin-layer chromatography. The result showed that the drug level in the brain was relatively constant when the dose was the median effective dose (ED50) for the test at those time intervals after administration.

The isolation and characterization of metabolites excreted in urine of rat were studied following oral administration of 14C-glipizide. Five metabolites and a small amount of the unchanged compound were isolated from urine samples of rat and their structures were elucidated by thin-layer chromatography and by various spectroscopic analysis. As the results, 3-cis-, 4-trans-hydroxycyclohexyl derivatives, decyelohexyl derivative, hydroxymethyl derivative and hydroxyethyl derivative were identified or suggested.The relative amount of each metabolite excreted in the urine differed remarkably according to the species of animals used: in rat and mouse major metabolites were 4-trans-, 3-cis-hydroxycyclohexyl derivatives and decyclohexyl derivative; in guinea-pig 4-trans-, 3-cis-hydroxycyclohexyl derivatives and hydroxymethyl derivative; and in rabbit hydroxymethyl derivative. In dog, cat and monkey N- (4-carboxymethyl-benzene-sulfonyl) -N'-cyclohexyl-urea was suggested to be a major metabolite.

14C-L-dopaを40mg/kg (3.4μCi/マウス) の割合で経口投与し, 経時的にcatecholと未変化のL-dopaの組織分布をしらべるとともに, 6時間尿中に排泄された放射性化合物について検討した。その結果, 血漿, 脳, 肝臓, 膵臓で放射能取込みは投与後20分をピークとし経時的に減少した。しかし, 副腎は20, 60, 360分の各時点において一定の放射能濃度を示した。一方, catecholの経時的変化もこれとまったく同様であり, しかも副腎中のcatecholは大部分catecholamineであることを認めた。脳中のcatecholamineの占める割合は副腎を除く組織の間で最も高かった。未変化のL-dopaはそれぞれの組織においてごくわずかであった。尿中放射性化合物のうち最も多い代謝物はhomovanillic acid (44%) , ついで抱合体は38%を占め, catecholはわずか15.1%であった。このcatecholはnoradrenaline (4.1%) , adrenaline (3.2%) , dihydroxyphenyl acetic acid (2.8%) , dopa (1.75%) , dopamine (1.45%) , その他 (1.8%) から成ることを明らかにした。一方, 抱合体はL-dopa (12.8%) , homovanillic acid (6.1%) , dopamine (5.6%) , adrenaline (4.3%) , noradrenaline (2.7%) , dihydroxyphenyl acetic acid (2.2%) 等から成ることを認めた。

Absorption, excretion and metabolism of d-cis-3-acetoxy-5-[2-(dimethylamino) ethyl]-2, 3-dihydro-2-(p-methoxyphenyl)-1, 5-benzothiazepin-4 (5H)-one hydrochloride (CRD-401) were studied in rats. CRD-401 was found to be absorbed rapidly and almost completelyfrom the digestive tract, the half-life for absorption being 26 min.More than 90% of the radioactivity after oral administration of 14C-CRD-401 wasrecovered from the feces and urine within 72 hours. The feces is the major excretoryroute since approximately 60% of the total radioactivity recovered appeared in the 72hour feces and 65% of the administrated radioactivity was excreted in the 24 hour bile.CRD-401 was extensively metabolized by rat since only 0.1% of the drug wasrecovered unchanged in the 24 hour urine and bile. Metabolic pathways of CRD-401 consisted of deacetylation, N-demethylation, O-demethylation, hydroxylation andN-oxidation. Major metabolites in urine and bile were deacetyl-O-demethyl-CRD-401, deacetyl-N, O-demethyl-CRD-401, and deacetyl-N, O-demetyl-methoxyl-CRD-401. Thepresence of N-oxide analogs of CRD-401 as minor metabolites was demonstrated inurine but not in bile.

ラットにおけるdibutyrylated trimetoquinol (BAQ-509) およびtrimetoquinol (AQL-208) の吸収, 分布, 排泄, 代謝について検討した結果, 3H-BAQ-509は3H-AQL-208よりも速やかに吸収され, 前者の吸収半減期は80分であったのに対し, 後者のそれは190分であった。両化合物を投与し20分時点における気管支拡張作用を示すAQL-208の体内分布量において前者は後者にくらべ血液, 肝, 腎で2～11倍であった。3H-BAQ-509投与48時間までに排泄された尿中の放射能は投与量の67%であり, 糞中には29%であった。一方, 4時間までに排泄された尿中の代謝物を検索すると, 未変化の3H-BAQ-509は0.11%にすぎず, 69.3%がAQL-208のグルクロン酸抱合体であり, 29.3%がmethoxy-AQL-208のグルクロン酸抱合体であった。