著者

野口 英世

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.10, no.3, pp.407-412, 1995 (Released:2007-03-29)

参考文献数

14

著者

大石 孝義 西家 弘佳 小林 弘幸 小林 智

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.10, no.5, pp.683-688, 1995 (Released:2007-03-29)

参考文献数

7

被引用文献数

2 1

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イヌに 14C-KW-4679 を 1mg/kg 経口投与後の吸収および排泄について検討し,以下の結果を得た.1.血漿中放射能は投与後 1.13時間に最高濃度(723.2ng eq,/ml)を示した後,おおむね一相性に消失し,t1/2 は4.53時間であった.2.14C-KW-4679 の血球移行率は投与後2時間から12時間まで31.7-35.5% とおおむね一定値を示した.3.in vivo における血清蛋白結合率は投与後 0.5時間から12時間まで 53.1-56.8%とおおむね一定であった.4.投与後168時間までに尿中に 73.4%,糞中に 22.9% が排泄され,総累積排泄率は 96.3% であった.大部分は投与後48時間までに排泄された.

著者

Maika KISSEI Tomoo ITOH Tomoya NARAWA

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.29, no.5, pp.367-372, 2014-10-25 (Released:2014-10-25)

参考文献数

45

被引用文献数

7

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Folic acid (FA) is a water-soluble vitamin, and orally ingested FA is absorbed from the small intestine by the proton-coupled folate transporter (PCFT). In the present study, we investigated whether epigallocatechin gallate (EGCG), one of the tea catechins, affects the transport of FA by PCFT. EGCG inhibited the uptake of FA into Caco-2 cells and human PCFT-expressing HEK293 cells (PCFT-HEK293 cells). The initial rate of uptake of FA into PCFT-HEK293 cells followed Michaelis–Menten kinetics (Km = 1.9 µM). Dixon plots revealed that PCFT-mediated FA uptake was competitively inhibited by EGCG (Ki ≒ 9 µM). The uptake of the PCFT substrate methotrexate (MTX) was competitively inhibited by EGCG as well (Ki ≒ 15 µM). In conclusion, it is suggested that when FA or MTX is ingested with tea, it is likely that the intestinal absorption of these compounds by PCFT is inhibited, which could result in insufficient efficacy.

著者

緒方 宏泰

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.15, no.5, pp.461-466, 2000 (Released:2007-03-29)

参考文献数

1

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The clinical significance of the changing of plasma protein binding of drug was discussed. Blood concentration of free drug equilibrated with that at the site of action can be used as a useful tool for monitoring pharmacotherapy. The significant increase of blood concentration of free drug may be produced in a very restricted case which is described in detail in this article. However, it should be emphasized that the changing of concentration of total drug in blood does not parallel with that of free drug. Although the changing of plasma protein binding seems to be a minor factor in most of clinical cases, we should notice the role of protein binding which covers the changing of free drug when the monitoring using total drug concentration is performed.

著者

有吉 範高 布谷 憲一 高橋 由紀 宮本 昌美 醍醐 聡 梅津 有理 横井 毅 木村 寛三 Philippe BEAUNE 鎌滝 哲也

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.15, no.1, pp.57-61, 2000 (Released:2007-03-29)

参考文献数

28

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CYP2A6 has been characterized as a coumarin 7-hydroxylase in humans. A large interindividual difference in the activity of coumarin 7-hydroxylation suggested an existence of genetic polymorphism of this enzyme. In fact, CYP2A6*2 variant allele which has T→A substitution, leading to amino acid change from Leu160 to His160, has been found in Caucasian population as the most frequent mutation in poor metabolizers (PM) of coumarin. Although several drugs used clinically or under development such as fadrozole, losigamone and methoxyflurane are recognized at present to be good substrates of CYP2A6, no specific substrate of this CYP isoform has been known until we found a drug, SM-12502. In the phase I trial, 3 out of 28 Japanese subjects were classified as PM of the drug. In vitro studies demonstrated that CYP2A6 played a major role on the metabolism of the drug. Genomic analysis revealed that the PM phenotype was caused by the presence of a novel CYP2A6 gene variant which lacks the entire region of open reading frame encoding the enzyme in the PM. Thus, we designated the variant as “deletion-type” allele. We examined the frequency of individuals carrying homozygous deletion by a genotyping method established in our laboratory. Thus, the frequency was estimated to be 3-4% in Japanese. We found another CYP2A6 gene variant whose 60 bp in the 3'-untranslated region was substituted by the corresponding region of the CYP2A7 pseudogene. This variant was designated as “conversion-type” allele. We found that the allele frequency of the conversiontype was comparable to that of wild-type, CYP2A6*1 allele in Japanese. We also compared the frequency of the CYP2A6*2 allele as well as the deletion and the conversion alleles between Japanese and Caucasian. Consequently, a marked interracial difference in the frequency of the genetic variants of the CYP2A6 gene was observed. These results give an interesting insight into racial difference in response to drugs and evolution of the CYP2A gene subfamily in humans.

著者

平塚 明

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.15, no.1, pp.20-26, 2000 (Released:2007-03-29)

参考文献数

55

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This article describes sources and mechanisms of formation of α, β-unsaturated aldehydes, their reactivity with respect to glutathione and amino-groups, their toxicity based on interaction with sulfhydryl and amino targets in cells, and modulation of gene expression by the aldehydes. Among the many different aldehydes generated durimg lipid peroxidation, 4-hydroxy-2 (E)-nonenal (4-HNE) is one of the major products and has been shown to have a number of adverse biological effects. All previous studies on biological and toxicological effects of 4-HNE have been carried out using its racemate. Therefore, nothing has been known of which enantiomer of the racemate is more toxic, more reactive with biomacromolecules, or more readily detoxified by glutathione S-transferase (GST) and alcohol dehydrogenase (ADH) than the other. This article also describes the first evidence for the marked enantioselectivity by 4-HNE enantiomers in the irreversible inactivation of the glycolytic enzyme, rabbit muscle glyceraldehyde-3-phosphate dehydrogenase, and in their detoxification by rat liver cytosolic GST A4-4 and ADH.

著者

廣津 京一 衛藤 公洋 有馬 徳行 西峯 秀夫

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.14, no.2, pp.92-104, 1999-04-30 (Released:2007-03-29)

参考文献数

9

被引用文献数

1

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14C標識塩酸アザセトロソをラットに経口投与して,吸収,分布,代謝および排泄について検討した. 1.塩酸アザセトロンは主として小腸から吸収された.吸収率は,胆管痩ラットにおける胆汁中および尿中放射能排泄率の合計から91%以上と算出された.0.4,2および10mg/kgのいずれの投与群でも,血漿中放射能濃度は投与後0.6時間以内にCmaxを示し,6.7-8.0時間のt1/2Zで消失した.t1/2Zには投与量による差異はなかったが,CmaxおよびAUC0-∞は投与量比以上に増加した. 2.投与後,放射能は速やかに各組織に移行し,ほとんどの組織で投与後1時間に最高濃度を示した.この時点では消化管および膀胱の濃度が高く,ついで,肝臓,下垂体,腎臓,顎下腺,膵臓および肺の濃度が高かった.投与後24時間では多くの組織で放射能濃度が検出限界以下であった. 3.0.4,2および10mg/kgを投与すると,いずれの投与量でも投与後48時間以内に投与量の96%以上が排泄され,体内からの放射能の消失は速やかであった.2mg/kg投与時の投与後96時間では体内に放射能を検出できなかった.胆管痩ラットに投与すると,投与量の増加と共に,尿中放射能排泄率が有意に増加し,胆汁中放射能排泄率は有意に減少した.胆汁中に排泄された放射能の約24%が腸肝循環により再吸収された. 4.尿中および糞中,ならびに胆汁中の代謝物には投与量による質的な差異はなかったが,量的な差異がみられた.胆管痩ラットの尿中にはアザセトロンおよびM1が多く排泄され,胆汁中にはM1およびM3が多く排泄された.10mg/kg投与では,0.4および2mg/kg投与時よりもアザセトロンの尿中排泄率が有意に増加し,主代謝物であるM1およびM3の胆汁中排泄率が有意に減少した.食餌により吸収率は低下したが,代謝の変動はなかった. 5.以上の結果から,14C標識塩酸アザセトロンの非線形動態の原因は,主として,アザセトロンの肝臓での代謝能の飽和であることが示唆される.

著者

西峯 秀夫 三浦 誠二 衛藤 公洋 岡部 次夫 有馬 徳行

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.7, no.6, pp.661-673, 1992-12-25 (Released:2007-03-29)

参考文献数

4

被引用文献数

1

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The plasma concentration, distribution, metabolism and excretion of 14C-Y-25130 were investigated in rats after intravenous administration. 1. Plasma levels of radioactivity (14C) decreased multiexponentially at the dose levels of 0.4, 1, 2, 10mg/kg, and the terminal half-lives (t1/2z) were 8.4 -9.5 hours. No dose or sex differences in t1/2z were observed. The areas under the plasma level-time curve were approximately proportional to the dose. Tissue levels of 14C were high in the liver, lung, kidney, pituitary gland, submaxillary gland, pancreas, stomach, adrenal, bone marrow, thyroid and spleen. Radioactivity rapidly disappeared from all tissues and was not detected in carcasses 96 hours after administration, suggesting no accumulation of 14C. 2. Binding rates of 14C to plasma proteins were 42.8-44.6% during 0.25-2 hours after administration. 3. Four days after administration to male rats at a dose of 1 mg/kg, urinary and fecal excretion of 14C were 45.5% and 52.9% of administered dose, respectively. At this dose, urinary excretion was much higher in female rats than in male rats. The excretion in male rats increased significantly at the highest dose level. Unchanged drug was found mainly in urine, while the unchanged drug, M1 and M3 were present in feces. The amount of unchanged drug in urine was much higher in female rats than in male rats. This amount increased at the highest dose level in male rats. 4. Fourty eight hours after administration to bile-duct cannulated male rats, 42.0% of the dose was excreted in bile and 12.8% in feces. This result indicates that another direct excretion route to the gastrointestinal tract exist besides the bile. About 13% of 14C excreted in bile was reabsorbed from the intestines by the enterohepatic circulation.

著者

西峯 秀夫 三浦 誠二 黒板 孝信 川北 武志 有馬 徳行

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.7, no.6, pp.771-785, 1992-12-25 (Released:2007-03-29)

参考文献数

8

被引用文献数

2

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1.14C標識化合物を静脈内投与して,Y-25130のイヌにおける代謝を検討した.尿,糞および血漿中には未変化体のほかに少なくとも4種の代謝物が検出された.主代謝物は尿中ではM1,M2およびM4,糞中ではM1およびM5であった.ラットにおいて生成した代謝物M3はイヌでは検出されなかった. 2.イヌの尿中から4種類,ラットの尿中から1種類の代謝物をそれぞれ単離し,これら代謝物を合成標品の核磁気共鳴および質量スペクトルとの比較により同定した.Y-25130はN-脱メチル化反応,アザビシクロオクタン環の窒素原子の酸化反応,これらの反応の組み合わせ,オキサジン環の開裂およびベンゼン環の水酸化反応により代謝された.

著者

西内 偉格 吉田 真里子 木下 春樹 高岸 靖 山田 秀雄 稲沢 和博 中野 正行 能登谷 満 長谷川 博司 水平 敏知 菅野 浩一

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.5, no.2, pp.179-197, 1990 (Released:2007-03-29)

参考文献数

4

被引用文献数

7

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The distribution, excretion and metabolism of recombinant human interleukin-2 (S-6820) were studied using 125I-labeled compound (125I-S-6820)1. At 5min after intravenous injection of 125I-S-6820 to male and female rats, high radioactivity was observed in the kidney. Radioactivities in the other organs were lower than the serum level. Results obtained by whole-body autoradiography showed that high concentrations of radioactivity were found in the cortex renis.2. At 5min after intravenous injection of 125I-S-6820 to 20-th day pregnant rats, no radioactivities were detected in the amniotic fluid and fetus.3. Within 24hr after intravenous injection of 125I-S-6820, 78% and 1 % of administered radioactivity were excreted in the urine and feces, respectively. However, 98% of excreted radioactivity in the urine was not precipitated with trichloroacetic acid.4. In the kidney after intravenous injection of 125I-S-6820, a low molecular weight degradation products of 125I-S-6820 were observed as revealed by gel filtration radio-chromatography. In addition, micro-autoradiogram of cortex renis after intravenous injection of 125I-S-6820 showed that S-6820 was likely to be ultrafiltrated by the glomerulus and absorbed by proximal tubules. S-6820 appeared to be degraded in the kidney.

著者

西内 偉格 甲斐 包子 吉田 真里子 高岸 靖 山田 秀雄 永井 修吾 刈谷 巽 佐々木 緊

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.5, no.2, pp.165-177, 1990 (Released:2007-03-29)

参考文献数

14

被引用文献数

5

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The absorption, distribution, excretion and metabolism of recombinant human interleukin-2 (S-6820) were studied following intravenous or subcutaneous injection at a dose of 5×105U/kg to rats. Concentrations of S-6820 in serum, tissues and other body fluids were measured by a bioassay and an enzyme immunoassay. 1. After intravenous injection of S-6820 to rats, serum levels of S-6820 decreased biphasically and the half-lives of the α phase and β phase were 2. 4 min and 16min, respectively. 2. Absorption ratio after subcutaneous injection of S-6820 was about 37%.3. After repeated intravenous injection of S-6820 once a day for 5 days, the levels of S-6820 in serum and tissues reached the same levels as after single administration. No accumulation was observed.4. After intravenous injection of S-6820, especially high level was observed in the kidney, however, it decreased rapidly (t1/2=11min). The levels of S-6820 in the other organs (spleen, lung, heart and liver) were lower than the serum level.5. After intravenous injection of S-6820 to 20-th day pregnant rat, S-6820 in the amniotic fluid and fetus was not detected.6. After intravenous injection to lactating rats, the transfer of S-6820 from blood to milk was minimal.7. A little of S-6820 was found in the bile by EIA. S-6820 was not detected in the urine by EIA method.8. The disappearance rates of S-6820 in rats changed from t1/2(β)=0.41hr in sham operated rats to t1/2(β)=1.57hr in rats with renal excision. The kidney appeared to be the main metabolic site.

著者

中川 明彦 谷島 ゆきみ 高萩 英邦 中村 皖一 島田 幸雄 長沼 英夫 塩谷 宏明 川原 幸則

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.2, no.2, pp.113-121, 1987 (Released:2007-03-29)

参考文献数

12

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GC/MSによるカルバサイクリン誘導体,CS-570のイヌ血漿中定量法を確立した.本法はODSおよびSiミニカラムによるclean-up法とメチル-DMiPS誘導体化を用いることにより,1ng/mlのCS-570を定量できた. CS-570をイヌに静注および持続静注し,その体内動態を解析した.その結果,CS-570の血漿中半減期は約10分と極めて短く,速やかに循環血流から消失することが明らかになった.また持続静注を行うと,投与開始後15分で定常状態の95%に到達することが判明した.

著者

菅野 浩一 溝尻 顕爾 江角 凱夫 高市 松夫 東条 英晃 横島 徹熹

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.2, no.3, pp.237-246, 1987 (Released:2007-03-29)

参考文献数

6

被引用文献数

2 1

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14C-Sch-19927を30mg/kgで雄性イヌに単回あるいは10回反復経口投与後の吸収,代謝および排泄について検討した. 1.単回投与後の血漿中放射能濃度は,投与後2時間に最高(15.22μg/ml)を示した後,8時間まで半減期4.43時間で消失した.投与後2時間の血漿中放射能の26%は未変化体であり,主な代謝物としてMD1が40%,M3が25%認められた.イヌ血漿のin vitro蛋白結合率は,0.1および1μg/mlでは90%以上であったが,10μg/mlでは60%であった.ヒト血漿の蛋白結合率は,いずれの濃度でも約70%であった.In vivoでのイヌ血漿蛋白結合率は,投与後2時間に35%を示した後,経時的に増加し,投与後24時間では69%となった. 2.単回投与後120時間までの尿中に66%,糞中に32%の放射能が排泄された.尿中放射能のうち,未変化体は6%であり,主代謝物としてMD1が52%,M3が18%認められた.β-Glucuronidase水解により,M3は全量が,MD1は一部がSch-19927に分解されたが,これはlabetalolのイヌ尿中主代謝物の性質と一致することより,M3はSch-19927のフェノール性グルクロナイドであり,MD1はアルコール性グルクロナイドであると推定された. 3.反復投与期間中,各回投与後24時間の血漿中放射能濃度は,投与回数に伴う濃度変化を示さなかった.最終回投与後の血漿中濃度は,投与後1.5時間に最高値(16.99μg/ml)を示したのち,8時間まで半減期7.12時間で消失し,単回投与に比べて消失は遅くなった.最終回投与後2時間の血漿中放射能の32%は未変化体であり,MD1が28%,M3が17%認められた. 4.反復投与期間中,尿中放射能排泄率は投与回数に伴う変化を示さなかったが,糞中排泄率は5回投与後まで増加した.最終回投与後120時間までの尿中に65%,糞中に31%の放射能が排泄された.尿中には,1回投与の場合と同じ割合の未変化体,主代謝物MD1およびその他の代謝物が検出された.

著者

東 純一

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.14, no.3, pp.256-259, 1999-06-30 (Released:2007-03-29)

著者

千葉 寛

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.11, no.3, pp.294-296, 1996-06-30 (Released:2007-03-29)

参考文献数

3

著者

池田 和正 増田 啓年 吉末 訓弘 東岡 喜作子 松島 英司 永山 績夫 川口 安郎

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.12, no.6, pp.656-667, 1997-12-31 (Released:2007-03-29)

参考文献数

16

被引用文献数

1

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S-1の動物種差について明らかにするためにマウス,ラットおよびイヌを用いたS-1の動態試験を試みた.また,イヌにS-1の投与量を変えて経口投与した時の各未変化体とその代謝物についてpharmacokinetic parameterを算出し,用量依存性について検討した.1.マウス,ラットおよびイヌを用いたS-1の動態試験の結果,血漿中FTはいずれの動物種においてもCmaxに顕著な差は認められなかった.しかし,イヌのAUCは103155ng·hr/mlともっとも高く,ラットが53600ng·hr/ml,マウスは4180ng·hr/mlであった.この種差はT1/2値にも見られた.血漿中5-FUはマウスのCmax、が1081ng/mlと顕著に高く,ラットが282ng/mlともっとも低かった.しかしT1/2値はマウスがもっとも小さく,ラットおよびイヌは同程度であった.血漿中CDHPはマウスのCmaxが1815ng/mlと顕著に高かったものの,AUCはいずれの動物種においても顕著な差は見られなかった.血漿中OxoのCmaxおよびAUCはいずれもマウスで顕著に高く,ラットがもっとも低かった. 2.ラットおよびイヌのbioavailabilityを算出した結果,FTのbioavailabilityはいずれもほぼ100%であった.一方,CDHPはラットで36.8%,イヌでは27.0%であった.またOxoではラットが3.0%に対しイヌでは9.9%であった. 3.イヌを用いてFT,5-FU,CDHPおよびOxoの用量依存性について検討した.その結果,FT,CDHPおよびOxoについては用量に比例した推移を示すことが明らかになった.一方,5-FUは用量の増加率以上に濃度が高くなり,線形と仮定した場合の濃度に比べAUCは1.8倍から2.8倍の増加が認められた.これはS-1に配合されている5-FUの代謝酵素の可逆的な拮抗阻害剤であるCDHPが,投与量の増加に従いCmax,AUCが高くなることで5-FUの代謝阻害をより強め,長時間持続するため,5-FUの代謝クリアランスが低下したためであると推察される.

著者

鈴木 洋史

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.15, no.2, pp.151-158, 2000 (Released:2007-03-29)

参考文献数

42

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It has been reported that some transporters are located on the blood-brain and blood-cerebrospinal fluid barriers to exclude their substrates from the central nervous system. In this article, the molecular mechanism for the vectorial transport of xenobiotics is summarized particularly focusing on our own studies. In addition to MDR1 P-glycoprotein, we could suggest the significant role of multidrug resistance associated proteins in the drug disposition in the central nervous system. Moreover, the role of organic anion transporting polypeptides and organic anion transporters is discussed in relation to the transport studies in the blood-cerebrospinal fluid barrier.

著者

横井 毅 山本 優衣 柴田 文佳 鈴木 美紀恵 島田 典招 若杉 隆伸 山木 光男 山守 育雄 中島 美紀 山崎 浩史

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.15, no.supplement, pp.126-127, 2000 (Released:2007-03-29)

参考文献数

3

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Troglitazone, a new oral antidiabetic drug, has been reported to cause idiosyncratic hapatitis in certain individuals. The mechanism for hepatic failure was investigated with comparison between troglitazone and its metabolites and other thiazolidinedions. Oxidation pathway of troglitazone to a qunone-type metabolite was catalyzed mainly by CYP2C8 and CYP3A4 in human liver microsomes. Inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human CYPs were not potent. Autoimmune antigen was identified in patients with idiosyncratic hepatitis. Hepatic toxicity did not appear in troglitazone treated rats after modifications of sulfotransferase, gluclonosyl-trasferase, or glutathione S-transferase activities. Treatment of HepG2 cell lines with troglitazone and a quinone type-metabolite showed time- and concentration-dependent cytotoxicity. Troglitazone induced apoptotic cell death in HepG2 cells. Taking these results into consideration, the causal factor(s) for idiosyncratic hepatitis in human remained unclear.

著者

横井 毅 山本 優衣 柴田 文佳 鈴木 美紀恵 島田 典招 山木 光男 若杉 隆伸 山守 育雄 中島 美紀 山崎 浩史

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.16, no.2, pp.145-150, 2001 (Released:2007-03-29)

参考文献数

9

被引用文献数

1

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Troglitazone, a new oral antidiabetic drug, has been reported to cause idiosyncratic hepatitis in certain individuals. The mechanism for the hepatic failure was investigated with comparison between troglitazone and its metabolites and other thiazolidinediones, pioglitazone and rosiglitazone. Hepatic toxicity did not appear in rats in troglitazone-administered study after modifications of sulfotransferase and glucuronosyltrasferase activities and glutathione concentration. Oxidation pathway of troglitazone to a quinine-type metabolite was catalyzed mainly by CYP2C8 and CYP3A4 in human liver microsomes. Inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human P450s would not be potent, based on its low blood concentrations and high protein binding ratio. An autoimmune antibody against aldolase B was identified in two patients with troglitazone-induced idiosyncratic hepatitis. However, this antibody was also detected in some other hepatic diseases, in spite of no cases in health control subjects. Treatment of HepG2 cell lines with troglitazone and a quinone type-metabolite showed time and concentration-dependent cytotoxicity. Troglitazone induced apoptotic cell death in HepG2 cells characterized by internucleosomal DNA fragmentation and nuclear condensation. Taking these results into consideration, the causal factor (s) for idiosyncratic hepatitis in human remained unclear.

著者

天野 潤 平松 優佳 早川 直彦 加藤 基浩 岡野 健 木下 春喜 岡崎 彬

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.8, no.6, pp.1199-1212, 1993-12-30 (Released:2007-03-29)

参考文献数

31

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The metabolites of rG·CSF present in the serum were investigated in rats after intravenous administration of 125I-rG·CSF at the dose of 10μg/kg, or nonlabeled-rG·CSF at the dose of 100-400μg/kg. 1. Using gel filtration on the Superose 12 column, most of the radioactivity in rat serum at 30min after administration of 125I-rG·CSF was eluted at a point corresponding to molecular weight of 19kd, this point was the same as that of intact-rG·CSF. The radioactivity was immunoreactive with anti-rG·CSF antibody and showed biological activity against NFS-60 cell lines. At 2 and 6h after administration, the radioactivity present in the serum was eluted from the column at a point corresponding to molecular weight of 46kd and 19kd. The radioactivity corresponding to 46kd showed immunoreactivity, but was biologically inactive. 2. The SDS-polyacrylamide gel electrophoresis revealed that most of the radioactivity in the serum present at 30min after administration of 125I-rG·CSF was detected at a point corresponding to intact-rG·CSF (molecular weight of 19kd). The radioactivity was also detected at a point corresponding to molecular weight of 19kd and 5kd at 2h, 19kd, 14kd and 5kd at 6h after administration. 3. The chromatofocusing using Mono-P column showed that most of the radioactivity in the serum was focused at a point corresponding to isoelectric points of 5.8 and 5.5 at 30min after administration of 125I-rG·CSF, these points were related to monosialo-rG·CSF and disialo-rG· CSF, respectively. At 2 and 6h after administration, the radioactivity showing immunoreactivity was newly found at a point corresponding to isoelectric points of 5.2 and 4.5. 4. During immunoblotting of serum samples after administration of nonlabeled-rG·CSF, the presence of a band corresponding to molecular weight of 19kd was found in all sampling times after administration. Beside the band of 19kd, only bands at a point corresponding to molecular weight of 5kd and 14kd were detected at 6h after administration. 5. Based of the fact that only an intact form of rG·CSF exists at early stage after intrave nous administration of rG·CSF, and since 2h the metabolites which have not biological activity appeared in the serum, we have concluded that an intact form mainly participate in hematologic activity of rG·CSF in vivo.