Evaluation of Myopathy Risk for HMG-CoA Reductase Inhibitors by Urethane Infusion Method
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概要
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Purpose of the present study was to evaluate the myopathy risk using a urethane infusion method following oral administration of five kinds of commercial HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (HCRIs), (pravastatin (PV), simvastatin (SV), cerivastatin (CeV), atorvastatin (AV), and fluvastatin (FV)) alone or with coadministration of bezafibrate (BF). The solubility of HCRIs in various solvents was determined as a criterion of the physicochemical property. The plasma creatine phosphokinase (CPK) level as a marker of myopathy in normal rats was screened under urethane infusion after oral administration of HCRI alone or with BF coadministration. Also, renal tissue specimens were prepared and the myoglobin remaining in the tissue was visualized by the labeled avidin-biotin technique. The plasma CPK level in normal rats under urethane infusion following oral administration of five kinds of HCRI increased as the dose of HCRI increased, and coadministration of BF further increased the CPK level for each drug. The risk of myopathy evaluated from the CPK level was ranked as follows : CeV>FV>AV>SV>PV. Myoglobin deposition was observed in the cast of proximal tubules, cytoplasm of distal tubules and collecting ducts of rat kidney extracted from rats treated with HCRIs under urethane infusion. Histopathological findings showed that the extent of myoglobin deposition increased on coadministration of BF with each drug. The correlation was found for myopathy risk evaluated by CPK level using the urethane infusion method and drug lipophilicity, i.e., the water/n-octanol partition coefficient except for the case of SV. Histopathological findings for the kidney following HCRI treatment also reflected the CPK level in rats under urethane infusion.
- 公益社団法人日本薬学会の論文
- 2002-03-01
著者
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MATSUYAMA Kenji
School of Pharmaceutical Sciences, Mukogawa Women's University
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UCHIDA Takahiro
School of Pharmaceutical Sciences, Mukogawa Women's University
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Tanaka H
Faculty Of Pharmacy Meijo University
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Tanaka H
Department Of Agricultural Chemistry Faculty Of Agriculture Utsunomiya University
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Tanaka H
Department Of Bioresources Chemistry Faculty Of Agriculture Okayama University
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Tanaka H
Exploratory Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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Matsuyama Kenji
School Of Pharmaceutical Sciences Mukogawa Women's University
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Matsuyama Kenji
Department Of Clinical Pharmacy Faculty Of Pharmaceutical Sciences Mukogawa Women's University
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Toyama Hirohide
Institute For Chemical Research Kyoto University
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Tanaka Haruyuki
Chemical Branch Faculty Of Engineering And Kansai University High Technology Research Center Kansai
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Uchida Takahiro
School Of Pharmaceutical Sci. Mukogawa Women's Univ.
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Nishikata Mayumi
School Of Pharmaceutical Sciences Mukogawa Women's University
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TANAKA Hiromi
School of Pharmaceutical Sciences, Mukogawa Women's University
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NAKAGAWA Kimiko
School of Pharmaceutical Sciences, Mukogawa Women's University
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NAKAI Aki
School of Pharmaceutical Sciences, Mukogawa Women's University
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KONISHI Yuriko
School of Pharmaceutical Sciences, Mukogawa Women's University
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Tanaka Hiroyoki
Faculty Of Pharmaceutical Sciences Kyushu University
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Nakai Aki
School Of Pharmaceutical Sciences Mukogawa Women's University
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Nishikata M
School Of Pharmaceutical Sciences Mukogawa Women's University
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Yoshida K
Unit Of Chemistry Faculty Of Engineering And High Technology Research Center Kansai University
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Nakagawa Kimiko
School Of Pharmaceutical Sciences Mukogawa Women's University
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TANAKA Hiromi
Department of Physics Faculty of Education, Saga University
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