Identification of Cytochrome P450 Enzymes Involved in the Metabolism of FK228, a Potent Histone Deacetylase Inhibitor, in Human Liver Microsomes(Biopharmacy)
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概要
- 論文の詳細を見る
FK228 (FR901228, depsipeptide) is a potent histone deacetylase inhibitor currently in phase II clinical trials for cancer treatment. In the present study, the cytochrome P450 (P450) enzymes responsible for FK228 metabolism in human liver microsomes were investigated. Incubation with human liver microsomes in the presence of an NADPH-generating system revealed that FK228 is metabolized to at least 10 different metabolites. K_m and V_<max> values for FK228 disappearance were 20.3 μM and 561.9 pmol/min/mg protein, respectively. Further studies were performed at a substrate concentration of 10 μM (half the K_m value for FK228 disappearance). FK228 disappearance activities in human liver microsomes from 12 individuals strongly correlated (r^2=0.957) with testosterone 6β-hydroxylase activities, a marker enzyme activity of CYP3A4/5, but not with other P450 enzyme-specific activities (CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, and 4A). Among 14 recombinant heterologously expressed human P450s examined, CYP3A4 exhibited the highest activity of FK228 disappearance. CYP3A5, 1A1, 2B6, and 2C19 showed 16.8%, 5.2%, 1.6%, and 1.3% of the activity of CYP3A4, respectively. Other P450s showed no significant metabolic activity toward FK228. In addition, FK228 disappearance in human liver microsomes was markedly inhibited by ketoconazole, a potent CYP3A4 inhibitor, and an anti-CYP3A4 antibody. These results indicate that the metabolism of FK228 in human liver microsomes is catalyzed mainly by CYP3A enzymes, particularly CYP3A4.
- 公益社団法人日本薬学会の論文
- 2005-01-01
著者
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Kawamura A
Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.:(present Address)analysis And
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Shirage Toshifumi
Departmnet Of Pharmacolinetics And Drug Metabolism Pharma Ceutical And Pharmacolinetic Research Labo
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Shiraga T
Biopharmaceutical And Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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SHIRAGA Toshifumi
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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KAGAYAMA Akira
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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ISHIMURA Rika
Fujisawa Pharmaceutical Co., Ltd.
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TOZUKA Zenzaburo
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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ISHIMURA Rika
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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KAWAMURA Akio
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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Tozuka Zenzaburo
Biopharmaceutical And Pharmacokinetics Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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Ishimura Rika
Fujisawa Pharmaceutical Co. Ltd.
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Kagayama Akira
Biopharmaceutical And Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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Shiraga Toshifumi
Biopharmaceutical And Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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Kawamura Akio
Department Of Surgery Sapporo Hokuyu Hospital Research Institute For Artificial Organs Transplantati
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