Metabolism of Quazepam and its Metabolites in Humans: Identification of Metabolic Enzymes and Evaluation of Drug Interaction In Vitro.
Drug Metabolism and PharmacokineticsPublished 1 January 2001Open access
Hiroshi Fujisaki, Kyouichi HIROTSU, Takayuki Ogawa, Kouichi Mizuki, Hiroaki MIZUTA, Noriyuki Arima
Citations7
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TL;DR
The species of enzymes involved in human metabolism of quazepam and its metabolites M4 and M6 were clarified, and the effects of these compounds on activities of major human P450 isozymes were evaluated.
Abstract
クアゼパムならびにその代謝物M4およびM6について，ヒトにおける代謝酵素を明らかにするとともに，各種P450の活性に及ぼすこれら化合物の影響を検討した．代謝酵素の同定は9種の発現系P450(CYP1A2，CYP2A6，CYP2B6，CYP2C9，CYP2C19，CYP2D6，CYP2E1，CYP3A4およびCYP4A11)を用いてそれぞれの代謝反応に関与するP450分子種を検索した．また代謝に関与する主要なP450分子種を明らかにするため，ヒト肝ミクロソームを酵素源としてP450抗体およびP450抗血清を用いた阻害試験を行った．さらにクアゼパムからM4の代謝反応に関してはFMOの関与についても検討した．その結果，クアゼパムからM4への代謝にはCYP2C9およびCYP3A4の2分子種が関与することを明らかにした．また本代謝反応にFMOの関与はなかった．M4からM5への代謝はCYP3A4が，M4からM6への代謝は主としてCYP2C9およびCYP3A4が触媒することを明らかにした．さらにM6からM7への代謝はCYP3A4が触媒することを明らかにした．次にクアゼパム，M4およびM6がヒトの薬物代謝に関与する主要なP450(CYP1A2，CYP2A6，CYP2C9，CYP2C19，CYP2D6およびCYP3A4)による代謝に及ぼす影響，すなわち発現系P450を酵素源として各P450の指標酵素活性に及ぼす影響を評価した．その結果，検討したいずれのP450分子種に対してもクアゼパム，M4およびM6はほとんど影響を及ぼさないことを明らかにした．
Keywords
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