Amiodarone Increases the Accumulation of DEA in a Human Alveolar Epithelium-Derived Cell Line(Pharmacology)
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概要
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Amiodarone (AMD)-induced pulmonary toxicity (AIPT) is the most life-threatening side-effect of AMD treatment. N-Monodesethylamiodarone (DEA), an active metabolite of AMD, also exhibits cytotoxicity and tends to accumulate in the lung more intensively than AMD. In this study, we characterized the mechanism of DEA accumulation using A549 cells as a model of the alveolar epithelium. Typical ATP-depletion compounds caused an approximately 30% increase in the accumulation of DEA in A549 cells, although these effects were less than those in Caco-2 cells. Triiodothyronine (T_3), which exhibited an inhibitory effect on DEA efflux in Caco-2 cells, did not affect the accumulation of DEA in A549 cells. On the other hand, 100 μM AMD caused an approximately 200% increase in DEA content in A549 cells, although AMD accumulation was not affected by 100 μM DEA. Since the reducing effect of AMD on cellular ATP levels and that of FCCP were similar, the mechanism by which DEA accumulation is increased by AMD might be different from the ATP-dependent DEA efflux mechanism. The decrease in cell viability by DEA in the presence of AMD (IC_<50> value of DEA for A549 cell viability: 25.4±2.4 μM) was more pronounced than that by DEA alone (IC_<50> value: 11.5±3.0 μM). This further DEA accumulation by AMD might be a factor responsible for the greater accumulation of DEA than that of AMD in the lung in long-term AMD-treated patients.
- 社団法人日本薬学会の論文
- 2008-07-01
著者
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Kobayashi Masaki
Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmace
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Itagaki Shirou
Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmace
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Iseki Ken
Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmace
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Kobayashi Michiya
北海道大学医学部附属病院 薬剤
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SEKI Satoru
Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmace
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HIRANO Takeshi
Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmace
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Seki Satoru
Laboratory Of Clinical Pharmaceutics & Therapeutics Division Of Pharmasciences Faculty Of Pharma
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Iseki Ken
北海道大学医学部附属病院 薬剤
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Itagaki Shirou
Lab. Of Clinical Pharmaceutics & Therapeutics Div. Of Pharmasciences Fac. Of Pharmaceutical Sciences Hokkaido Univ.
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Kobayashi Michiya
Department Of Pharmacy Hokkaido University Hospital School Of Medicine Hokkaido University
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Iseki Ken
Department Of Clinical Pharmaceutics & Therapeutics Graduate School Of Pharmaceutical Sciences Hokkaido University
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Kobayashi Masaki
Laboratory I Nano Process Technology Department, Corporate Reseach and Development, Laboratories Research and Development Group, Pioneer Corporation, 1-1, Fujimi 6 chome, Tsurugashima-shi, Saitama 350-2288, Japan
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