著者

酒井 孝範 粟田 則男

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.2, pp.263-272, 1993-04-10 (Released:2007-03-29)

参考文献数

23

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The vagina is an important area of the reproductive tract. The vaginal route of administration of drugs may be a viable alternative to oral theraphy. But the vaginal preparations on the market are exclusively restricted to those are topically effective. Most of agents in vaginal preparations act directory on the vaginal membrane. Vaginal absorption is characterized by the avoidance of hepatic first pass effect, prolonged retention of the blood level and the variation throughout the reproductive cycle. In this minireview, the vaginal absorption of several drugs with low molecular weight is introduced from the standpoint of chemical structure, first pass effect and transport process. In addition, we discuss the vaginal absorption of prasterone sulfate(PS)in rats. PS is almost completely absorbed from the vagina. PS may be transported through vaginal membranes by both paracellular route and carriermediated process.

著者

久保田 隆廣 千葉 寛 伊賀 立二

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.69-74, 2001 (Released:2007-03-29)

参考文献数

34

被引用文献数

2 4

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Approximately 1% of Orientals and 7 to 10% of Caucasians lack the activity of cytochrome P450 (CYP) 2D6, and these individuals are known as poor metabolizers (PM). On the other hand, approximately 4% of Caucasians are PM of CYP2C19, while its frequencies are 18 to 23% in Orientals. These differences in the frequencies of PM seen in the different ethnic populations are mainly due to the differences in the distribution frequency of variously defective alleles of CYP2D6 and 2C19. Recent progress in molecular biology of CYPs has enabled the mechanism of CYP polymorphism to be elucidated and the polymerase chain reaction was developed for its genotyping. Our previous studies showed that the frequencies of CYP2C19*2, *3, CYP2D6*2, *5, *10, *14, and CYP2C9*3 among the Japanese subjects were 28.7, 13.2, 12.9, 6.2, 38.6, 2.2 and 2.1%, respectively. In this review, we compared the frequencies of these mutant alleles of CYPs seen in the Japanese population with those reported previously for other ethnic populations.

著者

伊賀 立二

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.309-314, 1996-06-30 (Released:2007-03-29)

参考文献数

4

被引用文献数

1 2

著者

川口 輝久 久保 正則 宮内 俊 秋山 仁 小富 正昭

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.9, no.5, pp.628-650, 1994 (Released:2007-03-29)

参考文献数

19

被引用文献数

2

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BOF-A2(3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5-fluorouracil)をラットに単回および反復経口投与後の主代謝産物である1-ethoxymethyl-5-fluorouracil(EM-FU),3-cyano-2,6-dihydroxy-pyridine(CNDP),5-fluorouracil(5-FU)の吸収,分布,代謝および排泄について検討した. 1.各代謝産物の血漿中濃度推移はSDおよびDonryu系雄性ラットで差は認められなかった. 2.投与量の増加にともなって各代謝産物のCmaxおよびAUCo.72比も増加したが,1000mg/kg投与群ではやや頭打ちになる傾向が認められた. 3.5-FUとCNDPの併用投与あるいはEM-FUとCNDPの併用投与の場合よりも,BOF-A2投与の場合が血漿中5-FU濃度は最も長く持続した. 4.絶食あるいは非絶食下に雄性ラットに単回経口投与後,EM-FUは非絶食下投与の方が,CNDPおよび5-FUは絶食下投与の方が高い血漿中濃度推移を示した. 5.雌雄ラットに単回経口投与後,EM-FUは雌が,5-FUは雄が高い血漿中濃度推移を示した. 6.担癌雄性ラットにおける血中5-FUは,正常ラットよりも低い濃度推移を示した.これらのEM-FU,5-FUの濃度推移の差は,主に,肝ミクロソームにおけるEM-FUから5-FUへの活性化酵素(EM-FU代謝酵素)活性の差により,CNDPの濃度推移の差は吸収の差によると考えられた. 7.雄性ラットに反復経口投与後7日目には,1日目に比べて,EM-FUが高い血漿中濃度推移を示し,5-FUが低い推移を示した. 8.雌雄ラットに単回経口投与後2~8時間に,EM-FU,CNDP,5-FUは消化管,腎臓などで血漿中よりも高い濃度を示したが,24時間までには速やかに減少した.また,雄性ラットでの反復投与において,各代謝産物ともに組織への蓄積性は認められなかった. 9.雄性ラットにシメチジンおよびシスプラチンをBOF-A2と同時投与した場合,BOF-A2単独投与群に比べて,EM-FUの血漿中濃度および尿中排泄率が増加し,5-FUの血漿中濃度および尿中排泄率は減少したことから,シメチジソおよびシスプラチンによるEM-FU代謝酵素活性の抑制が推察された. 10.雄性ラットに単回経口投与後48時間までに,EM-FUが6.8%,5-FUが17.9%,CNDPが58.4%尿中へ排泄された.糞中にはBOF-A2が6.6%検出された。また,胆汁中排泄率は各代謝産物ともにわずかであった. 11.雄性ラットに反復経口投与した場合,尿中へのEM-FUの排泄率は増加し,5-FUの排泄率は若干減少する傾向が認められた. 12.雄性ラットに3,10,30mg/kgの用量で1日1回14日間反復経口投与後,NADPH Cyto-chrome C reductase活性が用量依存的に減少し,また,30mg/kg投与では,DHUDase活性が増加した.

著者

高長 ひとみ 大西 綾子 内田 淳子 山田 志穂 松尾 浩民 森元 聡 正山 征洋 澤田 康文

雑誌

薬物動態 = Xenobiotic metabolism and disposition (ISSN:09161139)

巻号頁・発行日

vol.13, pp.S110-S111, 1998-10-23

著者

渥美 亮 鈴木 亘 吉田 伸子 伯水 英夫

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.5, no.2, pp.209-216, 1990 (Released:2007-03-29)

参考文献数

13

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To examine the drug interaction between LC9018 and tegafur, the tegafur was administered to LC9018 treated or control mice and plasma concentrations of tegafur and its active metabolite, 5-fluorouracil (5-FU) were monitored.1. In 300μg LC9018/animal (intravenous, i.v.) treated group, the maximum plasma level(Cmax) of 5-FU and the area under the curve (AUC)decreased to 43% and 64% of control values, respectively. On the other hand, no change was observed in tegafur level, suggesting that LC9018 inhibited the conversion of tegafur to 5-FU at this dose.2. In 300μg LC9018/animal (intrapleural, i. pl.) treated group, 5-FU level decreased to 55% of the control at 30min after administration. But the influence on the metabolism of tegafur was smaller compared to the intravenous treatment of LC9018.3. In 180μg/animal (i.v.), 150μg/animal (i.pl.) and 300μg LC9018/animal (subcutanous, s.c.) treated groups, both tegafur and 5-FU level did not alter compared to the control.4. From above results, influence of LC9018 on the metabolism of tegafur depends on the dose and the administration route (i.v.> i.pl.> s.c.). It is considered that LC9018 slightly affects the metabolism of tegafur at clinical dose (200μg/animal i.pl.).

著者

嶋田 薫

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.supplement, pp.152-153, 2001-09-17 (Released:2007-03-29)

参考文献数

10

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The Caco-2 human-epithelial cell line has been widely used as a tissue-culture model for permeability measurements to predict human oral absorption in the drug discovery stage. In my presentation I will address some of the strategic applications of the Caco-2 model. Physicochemical properties affect the permeability. For example, permeability tends to be underestimated in hydrophilic compounds. For determining the permeability of poorly soluble drugs, some solubilizing reagents or bovine serum albumin can be used. The expression of some carrier-mediated transport systems has been confirmed on Caco-2 cell monolayers; therefore, we should pay attention to evaluating compounds that may be substrates of the transporters. The pH of the medium also affects the result of this assay. Transport studies with an apical pH value at 6.0 or 6.5 showed better prediction of in vivo drug absorption in human. For compounds that are substrates of P-glycoprotein (Pgp), the use of a Pgp inhibitor resulted in a better estimate of absorption in humans. The results suggest that compounds can be ranked according to how well they are absorbed; namely, those with Papp less than 1×10-6cm/s (poorly absorbed), between 1×10-6cm/s and 1×10-5cm/s (moderately absorbed), and greater than 1×10-5cm/s (well absorbed). The data of the Caco-2 assays are sometimes different, however, from those in different laboratories due to fluctuations in permeability resulting from passages and culture conditions, even when using the same clone. For high throughput screening, the permeability in 96-well Caco-2 assay demonstrates a good correlation with known human absorption for a variety of compounds. This is comparable to a 24-well system. Automation machines can be successfully applied for Caco-2 assays. Several in silicostudies for the prediction of Caco-2 permeability have also been conducted. A database system to which scientists easily access should be developed in collaboration with information-technologyg roups.

著者

山田 安彦 櫻井 和子 中村 幸一 澤田 康文 伊賀 立二

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.3, pp.283-293, 1993-06-30 (Released:2007-03-29)

参考文献数

46

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It is well known that change in drug distribution occur in association with hepatic disease. The prediction of the variation in the volume of distribution of drugs at steady-state (Vdss) in hepatic disease is very useful for the planning of drug dosage regimens. In the present study, we tried to develop methodology for estimating Vdss in hepatic disease based on physiological pharmacokinetics. The following two methods were utilized to predict Vdss in hepatic disease (hepatic cirrhosis and hapatitis). Method 1 : Vdss in hepatic disease was predicted assuming that Vdss in hepatic disease is not different from that in the normal condition. Method 2 : it is assumed that hepatic disease could not lead to alterations in the tissue binding but in the plasma binding, Vdss in hepatic disease was calculated according to the mass balance equation (Vdss=7.2+7.8·fP+27·fp/fT ; where fP and fT are plasma and tissue unbound fraction, respectively) by using the data of Vdss and fp in normal condition and that in hepatic disease. In hapatic cirrhosis, a significant correlation between the observed and predicted values according to Method 1 was obtained with a slope of regression line of 0.79 (p<0.001). On the other hand, a significant linear correlation between the observed and predicted values according to Method 2 was obtained with a slope of 1.03 (p<0.001). Furthermore, a significant difference in percent errors between the two methods was observed (p<0.05). In hepatitis, same resuls were also obtained. In conclusion, it is suggested that the extent of intrinsic tissue binding of various drugs is little altered in hepatic disease. The prediction of the apparent volume of distribution in hepatic disease according to Method 2 was successful for most drugs studied and very useful for clinical use.

著者

松本 宜明 清水 万紀子 福岡 正道

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.452-460, 2000 (Released:2007-03-29)

参考文献数

42

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Recently, an increasing number of pharmaceutical scientists and clinical pharmacists have begun to focus on pharmacodynamics, which relates the time course of drug concentration to the time course of pharmacological effects. An integration knowledge of pharmacokinetics and pharmacodynamics is essential for the development of rational pharmacotherapeutics because pharmacodynamics and pharmacokinetics are able to determines the drug concentration required to produce the desired therapeutic effect and the drug dose regimen required to achieve the targeted drug concentration, respectively, by using various models. The general principles of the drug effect model are based on the reversible direct and indirect models. In this review, various models in terms of the time course of drug effects are presented and discussed.

著者

杉林 堅次

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.1, pp.71-80, 1987 (Released:2007-03-29)

参考文献数

37

被引用文献数

1

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Transdermal absorption of drugs, i.e. nitroglycerin and scoporamine, from marketed transdermal therapeutic systems (TTS) has been evaluated mainly according to T. Higuchi's theory. This theory, at first, was reviewed from the thermodynamic point of view. Much attention is paid to the enhanced transdermal absorption to expand the utility of TTS to many drugs and it becomes realistic by use of prodrugs as esters of viderabine, an antivirus drug, by the application of penetration-enhancers such as Azone, and/or by appearance of iontophoresis. Secondly, such enhancing systems were summarized theoretically and the differences between them and Higuchi's theory on the absorption rates were discussed. The route for transdermal absorption and its kinetic model might be modified in such enhancing systems, since the systems affect the skin barrier function. Reasonable absorption routes and skin model were discussed, thirdly. These three considerations could be useful for the development and evaluation of new TTS.

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

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.