Contribution of Human Hepatic Cytochrome P450 Isoforms to the Metabolism of Psychotropic Drugs(Biopharmacy)
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概要
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The metabolic activities of six psychotropic drugs, diazepam, clotiazepam, tofisopam, etizolam, tandospirone, and imipramine, were determined for 14 isoforms of recombinant human hepatic cytochrome P450s (CYPs) and human liver microsomes by measuring the disappearance rate of parent compounds. In vitro kinetic studies revealed that V_<max>/K_m values in human liver microsomes were the highest for tofisopam, followed by tandospirone>clotiazepam>imipramine, diazepam, and etizolam. Among the recombinant CYPs, CYP3A4 exhibited the highest metabolic activities of all compounds except for clotiazepam and imipramine. The metabolism of clotiazepam was catalyzed by CYP2B6, CYP3A4, CYP2C18, and CYP2C19, and imipramine was metabolized by CYP2D6 most efficiently. In addition, the metabolic activities of diazepam, clotiazepam, and etizolam in human liver microsomes were inhibited by 2.5μM ketoconazole, a CYP3A4 inhibitor, by 97.5%, 65.1%, and 83.5%, respectively, and the imipramine metabolism was not detected after the addition of 1 or 10μM quinidine, a CYP2D6 inhibitor. These results suggest that the psychotropic drugs investigated are metabolized predominantly by CYP3A4, except that CYP2D6 catalyzes the metabolism of imipramine. In addition, this approach based on the disappearance rate appears to be useful for the identification of the responsible CYP isoform (s) of older drugs, for which metabolic profiles have not been reported.
- 公益社団法人日本薬学会の論文
- 2005-09-01
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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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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Kagayama Akira
Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.:(present Address)analysis And
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NIWA Toshiro
Post-marketing Development Research Center, Fujisawa Pharmaceutical Co., Ltd.
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SHIRAGA Toshifumi
Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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ISHII Ikuko
Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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TAKAGI Akira
Post-marketing Development Research Center, 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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Ishii Ikuko
Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.:(present Address)analysis And
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Tokunaga Akira
First Department Of Surgery Nippon Medical School
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Niwa Toshiro
Post Marketing Product Development Astellas Pharma Inc.
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Kawamura Akio
Department Of Surgery Sapporo Hokuyu Hospital Research Institute For Artificial Organs Transplantati
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