Effects of Serotonin-3 Receptor Antagonists on Cytochrome P450 Activities in Human Liver Microsomes(Biopharmacy)
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概要
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The effects of three serotonin-3 (5-HT_3) receptor antagonists, azasetron, ondansetron, and ramosetron, on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, and CYP3A4-mediated testosterone 6β-hydroxylation activities in human liver microsomes were compared. Azasetron and ramosetron at a concentration of 1 or 10μM neither inhibited nor stimulated any of the metabolic activities. On the other hand, ondansetron competitively inhibited CYP1A2 and CYP2D6 activities, and the inhibition constants (K_i) were 3.2 and 21.0μM, respectively, which are much higher than the reported plasma concentrations after clinical intravenous or oral dosing. The free fractions of the three 5-HT_3 receptor antagonists in the incubation mixture estimated by ultracentrifugation were more than 68.6%. These results suggest that azasetron, ondansetron, and ramosetron do not cause clinically significant interactions with other drugs that are metabolized by CYPs via the inhibition of metabolism.
- 社団法人日本薬学会の論文
- 2006-09-01
著者
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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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Saito Miho
Astellas Research Services Co. Ltd.
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NIWA Toshiro
Post Marketing Product Development, Astellas Pharma Inc.
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YAMAMOTO Sachiko
Astellas Research Services Co., Ltd.
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KOBAYASHI Naoto
Product Marketing, Astellas Pharma Inc.
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IKEDA Kaoru
Product Marketing, Astellas Pharma Inc.
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NODA Yasuo
Post Marketing Product Development, Astellas Pharma Inc.
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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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Noda Yasuo
Post Marketing Product Development Astellas Pharma Inc.
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Ikeda Kaoru
Product Marketing Astellas Pharma Inc.
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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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Yamamoto Sachiko
Astellas Research Services Co. Ltd.
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Kobayashi Naoto
Product Marketing Astellas Pharma Inc.
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