著者

加藤 基浩 丹羽 一与 天野 潤 早川 直彦 神山 博 大久保 一三 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.4, pp.481-492, 1993-09-10 (Released:2007-03-29)

参考文献数

17

被引用文献数

1

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We studied the absorption, distribution, excretion and metabolism of 125I-EPOCH after single subcutaneous administration to rats. 1. The levels of immunoreactive rad ioactivity reached the maximum at 8 to 12 hours after dosing and declined monoexponentially with a half-life ranging from 5.77 to 7.47 hours at the doses of 0.5, 1, 5 and 25μg/kg. The MRT of immunoreactive radioactivity after sc dosing ranged from 13.83 to 17.01 hours at any dose levels. F value (AUCsc/AUCiv), which ranged from 0.31 to 0.48, tend to increase in proportion to the administered dose. 2. Most of tissues showed the highest level of total radioactivity at 10 hour after dosing. The level of radioactivity in tissues were lower, than that of serum, except the thyroid gland whose level was the highest. They declined parallel with disappearence of the radioactivity in serum. The level of radioactivity in brain was extremely low. The elimination half-life of radioactivity from the injection site was calculated to be 9h and 1.97% of the dose still remained there at 48 hour. 3. Until 96h after sc administration of 125I-EPOCH at the dose of 1μg/kg, urinary excretions of total, the TCA-precipitable and the immunoreactive radioactivity were 75.89%, 0.35%, 0.05%, respectively. Fecal excretion of total radioactivity was 2.97%, until 96h after dosing. 4. Gel filtration of the plasma showed that the radioactivity of low molecular weight was iodo ion, and that related to radioactivity of high molecular weight appeared mainly as an unchanged 125I-EPOCH.

著者

加藤 基浩 天野 潤 岡野 健 平松 優佳 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.1213-1218, 1993-12-30 (Released:2007-03-29)

参考文献数

15

被引用文献数

3

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To evaluate the role of the kidney in the elimination of rG·CSF, the pharmackinetics of rG·CSF was studied in rats upon removal of one (1/2-nephrectomized rat) or of two kidneys (nephrectomized rat). Plasma concentrations of rG·CSF were measured by enzyme immunoassay method. 1. The elimination half lives of rG·CSF in nephrectomized and 1/2-nephrectomized rats, which were 4.85h and 1.llh respectively, were longer than those in sham operated rats given rG·CSF 10μg/kg intravenously. Total nephrectomy and 1/2-nephrectomy resulted in 70% and 30% reduction of total body clearance of rG·CSF in rats, respectively. 2. The result suggested that the kidney is the major elimination site of rG·CSF.

著者

Masoud JAMEI Gemma L DICKINSON Amin ROSTAMI-HODJEGAN

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.24, no.1, pp.53-75, 2009 (Released:2009-02-28)

参考文献数

150

被引用文献数

300

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An increasing number of failures in clinical stages of drug development have been related to the effects of candidate drugs in a sub-group of patients rather than the ‘average’ person. Expectation of extreme effects or lack of therapeutic effects in some subgroups following administration of similar doses requires a full understanding of the issue of variability and the importance of identifying covariates that determine the exposure to the drug candidates in each individual. In any drug development program the earlier these covariates are known the better. An important component of the drive to decrease this failure rate in drug development involves attempts to use physiologically-based pharmacokinetics ‘bottom-up’ modeling and simulation to optimize molecular features with respect to the absorption, distribution, metabolism and elimination (ADME) processes. The key element of this approach is the separation of information on the system (i.e. human body) from that of the drug (e.g. physicochemical characteristics determining permeability through membranes, partitioning to tissues, binding to plasma proteins or affinities toward certain enzymes and transporter proteins) and the study design (e.g. dose, route and frequency of administration, concomitant drugs and food). In this review, the classical ‘top-down’ approach in covariate recognition is compared with the ‘bottom-up’ paradigm. The determinants and sources of inter-individual variability in different stages of drug absorption, distribution, metabolism and excretion are discussed in detail. Further, the commonly known tools for simulating ADME properties are introduced.

著者

杉山 雄一 塚本 友子 堀井 郁夫

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.16, no.supplement, pp.84-85, 2001-09-17 (Released:2007-03-29)

参考文献数

2

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Capecitabine, an orally administered triple prodrug of 5-FU shows tumor-preferential exposure of 5-FU by being sequentially metabolized to 5-FU by three enzymes, which show relatively specific organ expression. To investigate the mechanism of tumor-preferential exposure of 5-FU after oral administration of capecitabine, a physiologically based pharmacokinetic model describing the pharmacokinetic behaviors of capecitabine and its metabolites including 5-FU in humans was constructed. The factors that have the greatest influence on the pharmacokinetics of 5-FU after administration of capecitabine were clarified by sensitivity analyses. The sensitivity analysis demonstrated the exposure of tumor tissue to 5-FU depends mainly on the activity of both thymidine phosphorylase (producing enzyme of 5-FU from the precursor, 5'-DFUR) and DPD (eliminating enzyme of 5-FU) in tumor tissue, as well as blood flow rate in tumor tissue with saturation of DPD activity resulting in higher 5-FU AUC in tumor tissue. The therapeutic index of capecitabine was found to be at least 17 times greater than that of other fluoropyrimidine, including doxifluridine, the prodrug of 5-FU, and 5-FU over their respective clinical dose ranges.

著者

堀井 郁夫

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.10, no.supplement, pp.174-175, 1995 (Released:2007-03-29)

著者

TAYAMA Yoshitaka MORIYASU Aya SUGIHARA Kazumi OHTA Shigeru KITAMURA Shigeyuki

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.22, no.2, pp.119-124, 2007-04-25

参考文献数

41

被引用文献数

12

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In this study, the developmental changes and variability of aldehyde oxidase in postnatal rat liver were examined. Postnatal day 1, 7 and 14 rats showed little or no liver aldehyde oxidase activity, as evaluated in terms of the activities for oxidation of benzaldehyde to benzoic acid, <i>N</i>-1-methylnicotinamide (NMN) to <i>N</i>-1-methyl-2-pyridone-5-carboxamide (2-PY) and <i>N</i>-1-methyl-4-pyridone-3-carboxamide (4-PY), and methotrexate (MTX) to 7-hydroxymethotrexate (7-OH-MTX). However, these oxidase activities were markedly increased in liver cytosol from the rats after postnatal day 14. The activity was then maintained up to 6 weeks. The amounts of 2-PY and 4-PY formed from NMN were almost the same. The development of aldehyde oxidase activity toward benzaldehyde was closely correlated with that of oxidase activity toward NMN and MTX. The expression of aldehyde oxidase at postnatal day 14 was confirmed by Western blotting analysis. The density of bands of aldehyde oxidase was closely correlated with the oxidase activity toward benzaldehyde. The developmental changes of aldehyde oxidase activities during postnatal reflected the changes in the amount of the oxidase protein. Thus, aldehyde oxidase activity in rats rapidly increases from birth, reaching a plateau within 4 weeks, and is regulated by expression of the protein.<br>

著者

小栗 一太

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.136-142, 2000 (Released:2007-03-29)

参考文献数

17

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Here, I briefly review studies on an active metabolite of morphine and characterization of enzymes responsible for the formation of the glucuronide in our laboratory. Morphine has been used extensively in pain clinic and was found biotransformed mainly by glucuronidation to a major inactive glucuronide; morphine-3-glucuronide (M-3-G) and also to a minor active metabolite; morphine-6-glucuronide (M-6-G). The very potent metabolite has been attracted much interest in a role of morphine analgesia in humans. The pharmacokinetic results are now interpreted as demonstrating that the active glucuronide had a positive effect on the analgesia. Recently, researchers have disclosed the presence of an unique opioid receptor for the glucuronide. Our recent experimental evidence from expression of two cDNA clones of glucuronidating enzymes from guinea pig liver supported the view that the enzymes form hetero-oligomers by accessing a broader range of compounds as in the active metabolite than homo-oligomers. A natural follow-up to the present evidence would be to carry out for the genomic information in regulatory molymorphism in drug metabolism by glucuronidation.

著者

増田 啓年 池田 和正 東岡 喜作子 永山 績夫 川口 安郎 堀 勝行 益子 俊之 江角 凱夫

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.12, no.4, pp.289-300, 1997-08-30 (Released:2007-03-29)

参考文献数

7

被引用文献数

7

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ラットに[14C-FT]-S-1,[14C-CDHP]-S-1あるいは[14C-Oxo]-S-1を投与しその吸収および排泄について検討し,以下の結果を得た. 1.[14GFT]-S-1を投与した絶食雄性ラットでは,血液中放射能濃度は投与後1時間にCmax 6215 ng eq./mlを示したのち2相性を示して消失する傾向を示した.主排泄経路は尿中であり,投与後72時間までの尿中,糞中およびに呼気中にそれぞれ投与量の74.7%,1.6%および15.5%排泄された.また,投与後48時間までの胆汁中には投与量の4.3%が排泄された. 2.[14C-FT]-S-1を投与した絶食雌性ラットでは雄性ラットと比較して血液中放射能濃度および排泄率に大きな相違は認められなかった. 3.[14C-FT]-S-1を投与した非絶食雄性ラットでは吸収および排泄に食餌による大きな影響はなかった. 4.[14C-FT]-S-1注入後30分における消化管ループからの吸収率は十二指腸で96.0%,空腸で96.2%,回腸で91.4%,結腸で67.8%であった. 5.[14C-CDHP]-S-1を投与した絶食雄性ラットでは,血液中放射能濃度は投与後1時間にCmax 569 ng eq./mlを示したのち1相性を示して消失した.主排泄経路は尿中であり,投与後72時間までの尿中および糞中にそれぞれ投与量の74.8%および22.5%が排泄された.また,投与後48時間までの胆汁中には投与量の1.3%が排泄された. 6.[14C-CDHP]-S-1を投与した絶食雌性ラットでは雄性ラットと比較してCmaxは1.3倍,AUCは1.4倍であったが尿中への排泄率は9.8%少なかった. 7.[14C-CDHP]-S-1を投与した非絶食雄性ラットでは食餌により吸収率は低下した. 8.[14C-CDHP]-S-1注入後30分における消化管ループからの吸収率は十二指腸で18.2%,空腸で20.2%,回腸で12.1%,結腸で4.0%であった. 9.[14C-Oxo]-S-1を投与した絶食雄性ラットでは血液中放射能濃度は投与後1.3時間にCmax 947 ng eq./mlを示したのち2相性を示して消失した.主排泄経路は尿中であり,投与後72時間までの尿中,糞中および呼気中にそれぞれ投与量の70.7%,27.0%および3.0%排泄された.また,投与後48時間までの胆汁中には投与量の1.0%が排泄された. 10.[14C-Oxo]-S-1を投与した絶食雌性ラットでは雄性ラットと比較してCmaxは1.3倍,AUCは1.5倍であったが尿中への排泄率は16.6%少なかった. 11.[14C-Oxo]-S-1を投与した非絶食雄性ラットでは食餌により吸収率は低下し,血液中放射能濃度推移も絶食時と大きく異なった. 12.[14C-Oxo]-S-1注入後30分における消化管ループからの吸収率は十二指腸で20.4%,空腸で37.6%,回腸で18.6%,結腸で6.8%であった.

著者

川口 輝久 久保 正則 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.661-674, 1994 (Released:2007-03-29)

参考文献数

8

被引用文献数

1

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14C-BOF-A2(3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxyme-thyl-5-fluorouracil)をラットに単回および反復経口投与後の放射能,主代謝産物である1-ethoxy-methy1-5-fluorouracil(EM-FU),3-cyano-2,6-di-hydroxypyridine(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.絶食あるいは非絶食下に雄性ラットに単回経口投与後,血液中放射能濃度は絶食下投与の方が高い推移を示した. 2.雌雄ラットに単回経口投与後の血液中放射能濃度推移には顕著な性差は認められなかった. 3.雄性ラットに反復経口投与後7および14日目の血液中放射能のCmaxは,投与初日の各々,1.8,2.2倍に増加し,AUC0-24hrもほぼ同様の割合で増加した. 4.雌雄ラットに単回経口投与後,総放射能濃度のAUC0-24hr に対する5-FUあるいはEM-FUのAUC0-24hrの割合は,5-FU(雄 : 7%,雌 :5 %)で,EM-FU(雄 : 63%,雌 : 78%)であった.5.雌雄ラットに単回経口投与後2~8時間に,胃,小腸以外では,肝臓,腎臓,副腎,骨髄において血漿中よりも高い放射能濃度を示した.投与後12時間以降の放射能の消失は多くの組織において血漿中に比較して緩慢で残留する傾向が認められた. 6.雄性ラットに反復経口投与14日目の投与24時間以降の放射能の消失は多くの組織において緩慢であり,残留傾向が認められた.7。雄性ラットに非絶食下単回投与後7日目までに尿中へ47.1%,糞中へ41.1%,呼気中へ8.6%の放射能が排泄され,死体残存率は1.2%であった.尿,糞および呼気へ排泄された放射能のほとんどが投与後48時間までに排泄された.また,絶食下単回投与後48時間までの放射能の排泄率は,尿64.9%,糞13.1%,呼気11.8%で,非絶食下投与群との間に差が認められた.8.雄性ラットに14日間反復経口投与期間中の毎回投与後24時間ごとの放射能の排泄率は,尿が約40%,糞が約35~55%,呼気が約10%で,反復投与による変化はなかった. 9.絶食あるいは非絶食下に雄性ラットに単回経口投与後24時間までに尿中へ排泄された総放射能に対するEM-FUの割合は,絶食下13%,非絶食下56%で,5-FUの割合は,絶食下24%,非絶食下9%であった. 10.雄性ラットに非絶食下単回投与後48時間までの放射能の胆汁中への排泄率は4.5%で,そのうち約50%がEM-FUであった. 11.in vitroでの血漿蛋白との結合率は,EM-FUは,ラット34~46%,イヌ47~51%,ヒト27~38%,5-FUは,ラット14~21%,イヌ16~17%,ヒト14~17%,CNDPは,ラット53~58%,イヌ63~71%,ヒト67~69%であった.ラットに14C-BOF-A2を単回経口投与後4,24時間における放射能の血漿蛋白との結合率は各々,39,93%であった.

著者

川口 輝久 久保 正則 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.651-660, 1994 (Released:2007-03-29)

参考文献数

5

被引用文献数

1

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BOF-A2(3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5-fluorouracil)をイヌ,サルおよびモルモットに経口投与後の主代謝産物である1-ethoxymethyl-5-fiuorouracil(EM-FU),3-cyano-2,6-dihy-droxypyridine(CNDP),5-fluorouracil(5-FU)の血漿中動態および尿中排泄について検討した.また,安息香酸およびイソフタル酸の血漿中動態についても検討した. 1.イヌに絶食および非絶食下で単回経口投与後,EM-FUは8時間にCmaxを示したのち,各 々,19.4,48.2hrの長いT1/2で消失した.EM-FUおよびCNDPの血漿中濃度推移は絶食群と非絶食群との間で差は認められなかった.また,いずれの時間においても5-FUは血漿中には検出されなかった. 2.イヌに単回経口投与後の血漿中にはイソフタル酸が検出されたが,EM-FUおよびCNDPよりも低い濃度推移を示した. 3.サルに6,20mg/kg/dayの用量で反復経口投与時の投与初日において,EM-FU,CNDPおよび5-FUは投与量にほぼ対応した血漿中濃度を示した.各代謝産物ともに血漿からの消失は非常に遅く,20mg/kg投与群ではEM-FU,CNDPは各々,22hr,10hrのT1/2を示し,5-FU濃度は投与後24時間まで増加し続けた. 4.サルに反復経口投与した場合,5-FUのCmaxおよびAUC0-24hrは投与日数の増加とともに減少する傾向を示し,T1/2は短縮した. 5.サルに単回経口投与後の血漿中には安息香酸はいずれの時間においても検出されなかった。イソフタル酸は投与後1時間にCmaxを示し,6時間以降の消失は緩慢であった. 6.モルモットに単回経口投与後の血漿中には,5-FUおよび安息香酸はいずれの時間においても検出されなかった. 7,イヌに単回経口投与後72時間までの尿中排泄率は,EM-FU10.1%,CNDP30.1%で,5-FUは尿中へはほとんど排泄されなかった.サルに単回経口投与後96時間までの尿中排泄率は,EM-FU12.7%,5-FU7.1%,CNDP50.9%であった.イヌおよびサルともに各代謝産物の排泄はラットに比べて遅延する傾向にあった.

著者

小松 貞子 中井 弘司 高松 康雄 盛中 泰洋 渡辺 和俊 篠田 真樹 飯田 成宇

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.5, pp.451-462, 1996-10-31 (Released:2007-03-29)

参考文献数

14

被引用文献数

6 6

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MCI-186の代謝物および代謝の種差を明らかにするため,代謝物の検索,構造推定,尿中への未変化体および代謝物の排泄率,in vitro代謝について検討を行った.以下にその要約を示す. 1.MCI-86の主代謝物はいずれの動物およびヒトにおいてもMCI-186のsulfateおよびglucuronideであった.ラット,イヌの尿中ではMCI-186 sulfateが多く,ヒト尿中ではMCI-186 glucuronideが多く,種差が認められた. 2.いずれの種においても尿中排泄が主排泄経路であった.未変化体の尿中排泄率は投与量の3%以下とわずかであった.イヌやヒトでは尿中排泄量のほとんどが未変化体およびMCI-186のsulfate,glucuronideで説明できるのに対し,ラットでは未知の代謝物が尿中放射能量の20~27%と多く存在した.ラットの尿中排泄において大きな性差は認められなかった. 3.ラットおよびイヌの肝S9を用いたMCI-186のin vitro代謝においては,ラット,イヌともMCI-186 sulfate生成活性のほうがglucuronide生成活性よりも高く,またラットにおいてはいずれの生成活性も雄性ラットのほうが雌性ラットよりも高値であった.

著者

乗原 隆 加藤 譲 奥村 修造 小林 智 山本 光雄 池永 哲二 出口 隆志 平田 正

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.6, no.6, pp.887-897, 1991

被引用文献数

1

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KW-2228およびrhG-CSFを,10μg/kgカニクイザルに静脈内および皮下投与時の血漿中動態,白血球数増多作用について検討した.また,反復皮下投与についても検討した.<BR>1.KW-2228を単回静脈内投与により,末梢血白血球数(WBC)の著明な増加が認められた.WBCは,投与後12時間に最高値,投与前の約2倍を示し,24時間後においてほぼ投与前値まで回復した.一方,単回皮下投与においては投与後12時間に最大に達し,投与前値の約4倍を示した.反復皮下投与では投与を重ねるに従い,WBCは上昇し,10日目の12時間値では初回投与前の約6倍を示した.白血球の上昇は主に分葉核好中球の上昇によるものであった.rhG-CSFについても同様なWBC増多作用が認められ,KW-2228と有意な差は認められなかった.また,赤血球数および血小板数には大きな変動は認められなかった.<BR>2.血漿中KW-2228は,静脈内投与後二相性に消失し,このときの半減期は0.43±0.09時間(%alpha;),1.34±0.35時間(β)であった.rhG-CSFもKW-2228と同様に二相性の消失パターンを示したが,αおよびβ相の半減期はそれぞれ0.40±0.04,1.11±0.05時間であり,KW-2228に比較し短いものであった.<BR>3,血漿中KW-2228およびrhG-CSFは皮下投与後,共に2時間にC<SUB>max</SUB>13.20±3.76,8.37±2.81ng/mlを示し,その後一相性に消失した.このときKW-2228濃度は2,6,8,10,12時間においてrhG-CSF濃度に比べ有意に高く,1.5~2倍の血漿中濃度を示した.KW-2228およびrhG-CSFの消失相の半減期はそれぞれ2.03±0.64,1.34±0.49時間であった.<BR>10回反復投与後の血漿中KW-2228のC<SUB>max</SUB>は,初回投与に比べ約2/5に減少し,半減期も約2/3と短いものであった.また,AUCは初回投与の約1/4であった.rhG-CSFについてもほぼ同じ傾向であった.反復投与後の血漿中濃度においては,KW-2228とrhG-CSFの間に差は認められなかった.

著者

Susumu NAKADE Shinya UEDA Tomoya OHNO Kazuki NAKAYAMA Yasuyuki MIYATA Eiji YUKAWA Shun HIGUCHI

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.21, no.2, pp.133-139, 2006 (Released:2006-05-10)

参考文献数

15

被引用文献数

3

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This study aimed to assess the steady-state pharmacokinetics of pranlukast, a leukotriene receptor antagonist, in children with allergic rhinitis and bronchial asthma, and to clarify factors affecting apparent clearance (CL/F). A total of 192 plasma samples were obtained from 98 children (rhinitis 64, asthma 13, complications 21), aged 3-14 years in 2 clinical trials. Plasma concentration of pranlukast was determined by liquid chromatography connected with a tandem mass spectrometer and analyzed by a population approach using NONMEM program. The plasma concentration-time course of pranlukast was described by using a one-compartment model with the first-order absorption and lag time. The robustness of the population pharmacokinetic model was evaluated by using 200 bootstrap samples. The results of population pharmacokinetic analysis showed that only age was a factor affecting the CL/F per body weight, with CL/F decreasing with increasing age. No significant variation was seen in the CL/F between rhinitis and asthma. The interindividual variability in the CL/F and the residual variability were 19.7% and 48.4%, respectively. All the parameters fell within 10% of the bootstrapped mean. In conclusion, the results show that age is the most influential factor for explaining interindividual variability in CL/F, and the difference in diseases does not affect CL/F.

著者

Stephen CURRY

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.24, no.4, pp.342-357, 2009 (Released:2009-09-10)

参考文献数

100

被引用文献数

237 92

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Human serum albumin (HSA) is an abundant and highly soluble plasma protein with the capacity to bind a remarkably diverse set of lipophilic anionic compounds so that it fulfils important roles in the transport of nutrients, hormones and toxins. The protein attracts great interest from the pharmaceutical industry since it can also bind a variety of drug molecules, impacting their delivery and efficacy. Our understanding of the binding and transport properties of albumin has been transformed by structural studies of the protein, in which crystallographic analysis has played a leading role. This review summarises the main insights to have accrued from this work, highlighting the significant advances that have been made but also pointing out some of the challenges ahead. Since further progress is likely to benefit from increased structural scrutiny of HSA, methodological developments instrumental to the success of crystallographic analysis of the protein are discussed in some detail.

著者

檜垣 和孝

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

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

巻号頁・発行日

vol.16, no.2, pp.157-158, 2001-04-28

著者

Yune-Fang UENG Ching-Chin TSAI Wei-Sheng LO Chul-Ho YUN

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.25, no.6, pp.560-567, 2010 (Released:2011-01-14)

参考文献数

40

被引用文献数

13

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The roots of Sophora flavescens (Sf) have been widely used as a herbal medicine for the treatment of diarrhea, gastrointestinal hemorrhage, and eczema. Cytochrome P450 (P450) forms including CYP1A2, CYP2B, CYP2E1, and CYP3A participate in the oxidative metabolism of theophylline, which is an important bronchodilation agent with a narrow therapeutic index. To assess the interaction of Sf with theophylline, the effects of Sf extract on theophylline-metabolizing P450s and on the pharmacokinetic profile of theophylline were investigated in male Sprague-Dawley rats. Oral treatment of rats with the Sf extract caused dose-dependent increases of liver microsomal oxidation activities toward 7-ethoxyresorufin, 7-pentoxyresorufin, and nifedipine. However, nitrosodimethylamine N-demethylation activity was not affected. The ingestion of Sf extract stimulated theophylline 8-oxidation and N-demethylation activities. The increases of oxidative activities were in consensus with the elevation of the protein levels of CYP1A2, CYP2B1/2, CYP2C11, and CYP3A. Sf-treatment increased the clearance of theophylline and decreased the area under the concentration-time curve (AUC) and the area under the moment curve (AUMC). These results demonstrate that Sf reduces blood theophylline concentration through facilitating the elimination of theophylline. In patients taking Sf, possible P450 induction-induced drug interaction should be noted to decrease the risk of therapeutic failure or adverse effects resulting from the use of additional therapeutic agents.

著者

Thomas A. BAILLIE Allan E. RETTIE

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.26, no.1, pp.15-29, 2011 (Released:2011-03-03)

参考文献数

91

被引用文献数

111

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It is now widely appreciated that drug metabolites, in addition to the parent drugs themselves, can mediate the serious adverse effects exhibited by some new therapeutic agents, and as a result, there has been heightened interest in the field of drug metabolism from researchers in academia, the pharmaceutical industry, and regulatory agencies. Much progress has been made in recent years in understanding mechanisms of toxicities caused by drug metabolites, and in understanding the numerous factors that influence individual exposure to products of drug biotransformation. This review addresses some of these factors, including the role of drug-drug interactions, reactive metabolite formation, individual susceptibility, and species differences in drug disposition caused by genetic polymorphisms in drug-metabolizing enzymes. Examples are provided of adverse reactions that are linked to drug metabolism, and the mechanisms underlying variability in toxic response are discussed. Finally, some future directions for research in this field are highlighted in the context of the discovery and development of new therapeutic agents.