In Vitro Characteristics and in Vivo Plasma Disposition of Cisplatin Conjugated with Oxidized and Dicarboxymethylated Dextrans
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概要
- 論文の詳細を見る
In vitro release behavior and cytotoxic activity, and in vivo plasma disposition of newly synthesized macromolecular derivatives of cisplatin (CDDP) were investigated and compared with CDDP. The derivatives included oxidized dextran conjugate of CDDP (OX-Dex/CDDP) and dicarboxymethylated dextran conjugate of CDDP (DCM-Dex/CDDP).In vitro release of platinum complex from dextran conjugated CDDP was determined by an equilidrium dialysis method. These dextran conjugates showed sustained release of the platinum complex. In vitro release half-life for DCM-Dex/CDDP was significantly longer (4.5 times) than that for OX-Dex/CDDP. In vitro cytotoxic activity of CDDP and dextran conjugated CDDP against colon 26,mouse colon cancer cell line, was measured using the MTT assay method. OX-Dex/CDDP showed a similar cytotoxic activity to CDDP. However, both cytotoxic activities were markedly decreased when preincubated with the medium containing serum. On the other hand, DCM-Dex/CDDP retained residual cytotoxic activity at a significantly higher level than OX-Dex/CDDP after preincubation with the medium containing serum, although it showed the lowest cytotoxic activity. This indicated longer maintenance of the in vitro antitumor activity of DCM-Dex/CDDP in serum compared with OX-Dex/CDDP. Plasma disposition of CDDP and dextran conjugated CDDP was determined by intraveous administration to rats. Although the total platinum plasma concentration-time profile for OX-Dex/CDDP was similar to that for CDDP, its markedly higher profile was achieved when DCM-Dex/CDDP was administered. The values of the total platinum AUC and MRT, where AUC is the area under the platinum concentration-time curve and MRT is the mean residence time, for DCM-Dex/CDDP were 11.2 times and 4.8 times significantly higher than with OX-Dex/CDDP in plasma, respectively. DCM-Dex/CDDP also showed a significantly lower total clearance compared with OX-Dex/CDDP. These results from the in vivo experiments revealed that retention of DCM-Dex/CDDP in blood circulation was much greater than thet for OX-Dex/CDDP.DCM-Dex/CDDP thus has potential as a macromolecular derivative of CDDP for passive tumor targeting.
- 公益社団法人日本薬学会の論文
- 1999-07-15
著者
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中島 幹夫
佐賀大学医学部附属病院 手術部
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KANEMATSU Takashi
Second Department of Surgery, Nagasaki University School of Medicine
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NAKASHIMA Mikiro
Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry
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SASAKI Hitoshi
Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry
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Nakashima M
Dep. Of Clinical Pharmacy Graduate School Of Biomedical Sciences Nagasaki Univ.
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Nakashima Mikiro
Department Of Hospital Pharmacy Nagasaki University School Of Medicine
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Sasaki H
Dep. Of Hospital Pharmacy Nagasaki Univ. Hospital
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ICHIKAWA Masataka
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University
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Nakano M
Department Of Laboratory Medicine Nagasaki University School Of Medicine
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Ichikawa M
Healthcare Research Institute Wakunaga Pharmaceutical Co. Ltd.
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Sasaki Hitoshi
長崎大学 医歯学部病院薬剤部
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Sasaki Hitoshi
Department Of Basic Pharmaceutics Faculty Of Pharmaceutical Sciences Kyoto University
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Tomiyama Naoki
武庫川女子大学 薬学研究科
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Tomiyama Naoki
Departrment Of Neurosurgery University Of The Ryukyus School Of Medicine
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OHYA Yuichi
Department of Applied Chemistry, Faculty of Engineering and High Technology Research Center, Kansai
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OUCHI Tatsuro
Department of Applied Chemistry, Faculty of Engineering and High Technology Research Center, Kansai
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Kanematsu Takashi
Second Department Of Surgery Nagasaki University School Of Medicine
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ICHINOSE Katsuro
Second Department of Surgery, Nagasaki University School of Medicine
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MASUNAGA Tatsunori
Department of Applied Chemistry, Faculty of Engineering, Kansai University
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Ohya Y
Department Of Applied Chemistry Faculty Of Engineering Kansai University
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Ohya Yuichi
Department Of Applied Chemistry Faculty Of Engineering Kansai University
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Ouchi Tatsuro
Department Of Applied Chemistry Faculty Of Engineering Kansai University
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Tomiyama Naoki
Department Of Hospital Pharmacy Nagasaki University School Of Medicine
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Ichikawa Masataka
Department Of Hospital Pharmacy Nagasaki University School Of Medicine
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Ichikawa Masataka
Department Of Pharmacy Nagasaki University Hospital
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Masunaga Tatsunori
Department Of Applied Chemistry Faculty Of Engineering Kansai University
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Ichinose Katsuro
Second Department Of Surgery Nagasaki University School Of Medicine
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ICHIKAWA MASATAKA
Department of Hospital Pharmacy, Nagasaki University School of Medicine
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Nakashima Mikiro
Department of Clinical Pharmacy, Graduate School of Biomedical Sciences, Nagasaki University
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ICHIKAWA MASATAKA
Department of Chemical Engineering, Kyushu University
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