Effect of Antifungal Drugs on Cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 Activities in Human Liver Microsomes(Biopharmacy)
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概要
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The effects of five antifungal drugs, fluconazole, itraconazole, micafungin, miconazole, and voriconazole, on cytochrome P450 (CYP) 2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, and CYP3A4-mediated nifedipine oxidation activities in human liver microsomes were compared. In addition, the effects of preincubation were estimated to investigate the mechanism-based inhibition. The IC_<50> value against tolbutamide hydroxylation was the lowest for miconazole (2.0μM), followed by voriconazole (8.4μM) and fluconazole (30.3μM). Similarly, the IC_<50> value against S-mephenytoin 4'-hydroxylation was the lowest for miconazole (0.33μM), followed by voriconazole (8.7μM) and fluconazole (12.3μM). On the other hand, micafungin at a concentration of 10 or 25μM neither inhibited nor stimulated tolbutamide hydroxylation and Smephenytoin 4'-hydroxylation, and the IC_<50> values for itraconazole against these were greater than 10μM. These results suggest that miconazole is the strongest inhibitor of CYP2C9 and CYP2C19, followed by voriconazole and fluconazole, whereas micafungin would not cause clinically significant interactions with other drugs that are metabolized by CYP2C9 or CYP2C19 via the inhibition of metabolism. The IC_<50> value of voriconazole against nifedipine oxidation was comparable with that of fluconazole and micafungin and higher than that of itraconazole and miconazole. The stimulation of the inhibition of CYP2C9-, CYP2C19-, or CYP3A4-mediated reactions by 15-min preincubation was not observed for any of the antifungal drugs, suggesting that these drugs are not mechanism-based inhibitors.
- 公益社団法人日本薬学会の論文
- 2005-09-01
著者
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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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Niwa T
近畿大学 薬学部
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Takagi Akira
Post Marketing Product Development Astellas Pharma Inc.
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NIWA Toshiro
Post-marketing Development Research Center, Fujisawa Pharmaceutical Co., Ltd.
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TAKAGI Akira
Post-marketing Development Research Center, Fujisawa Pharmaceutical Co., Ltd.
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SHIRAGA Toshifumi
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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Tokunaga Akira
Post-marketing Development Research Center Fujisawa Pharmaceutical Co. Ltd.
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Niwa T
Post-marketing Development Research Center Fujisawa Pharmaceutical Co. Ltd.
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Tokunaga Akira
First Department Of Surgery Nippon Medical School
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Shiraga Toshifumi
Biopharmaceutical And Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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Niwa Toshiro
Post Marketing Product Development Astellas Pharma Inc.
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