Identification of Human Drug-Metabolizing Enzymes Involved in the Metabolism of SNI-2011
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概要
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In vitro studies were conducted to identify human drug-metabolizing enzymes involved in the metabolism of SNI-2011((±)-cis-2-methylspiro [1, 3-oxathiolane-5, 3'-quinuclidine] monohydrochloride hemihydrate, cevimeline hydrochloride hydrate). When ^<14>C-SNI-2011 was incubated with human liver microsomes, SNI-2011 trans-sulfoxide and cis-sulfoxide were detected as major metabolites. These oxidations required NADPH, and were markedly inhibited by SKF-525A, indicating that cytochrome P450 (CYP) was involved. In a chemical inhibition study, metabolism of SNI-2011 in liver microsomes was inhibited (35-65%) by CYP3A4 inhibitors (ketoconazole and troleandomycin) and CYP2D6 inhibitors (quinidine and chlorpromazine). Furthermore, using microsomes containing cDNA-expressed CYPs, it was found that high rates of sulfoxidation activities were observed with CYP2D6 and CYP3A4. On the other hand, when ^<14>C-SNI-2011 was incubated with human kidney microsomes, SNI-2011 N-oxide was identified as a major metabolite. This N-oxidation required NADPH, and was completely inhibited by thiourea, indicating that flavin-containing monooxygenase (FMO) was involved. In addition, microsomes containing cDNA-expressed FMO1, a major isoform in human kidney, mainly catalyzed N-oxidation of SNI-2011, but microsomes containing FMO3, a major isoform in adult human liver, did not. These results suggest that SNI-2011 is mainly catalyzed to sulfoxides and N-oxide by CYP2D6/3A4 in liver and FMO1 in kidney, respectively.
- 2001-11-01
著者
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YASUDA Hiroshi
Research Center for Radiation Protection, National Institute of Radiological Sciences
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Arisawa H
Research Institute Of Life Science Snow Brand Milk Products Co. Ltd.
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Arisawa Hirohiko
Research Institute Of Life Science Snow Brand Milk Products Co. Ltd.
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WASHIO Takuo
Research Institute of Life Science, Snow Brand Milk Products Co., Ltd.
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KOHSAKA Kazuhiro
Research Institute of Life Science, Snow Brand Milk Products Co., Ltd.
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Washio T
Research Institute Of Life Science Snow Brand Milk Products Co. Ltd.
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Kohsaka Kazuhiro
Research Institute Of Life Science Snow Brand Milk Products Co. Ltd.
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Yasuda Hiroshi
Research Center For Advanced Science And Technology University Of Tokyo
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Yasuda Hiroshi
Research Institute Of Life Science Snow Brand Milk Products Co. Ltd.
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Yasuda Hiroshi
Research Center For Advanced Science And Technology The University Of Tokyo
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