DIAZEPAM METABOLISM BY HUMAN LIVER-MICROSOMES IS MEDIATED BY BOTH S-MEPHENYTOIN HYDROXYLASE AND CYP3A ISOFORMS
DIAZEPAM METABOLISM BY HUMAN LIVER-MICROSOMES IS MEDIATED BY BOTH S-MEPHENYTOIN HYDROXYLASE AND CYP3A ISOFORMS
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DOI：
10.1111/j.1365-2125.1994.tb04336.x
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发表时间：
1994-08-01
影响因子：
3.4
通讯作者：
BIRKETT, DJ
中科院分区：
文献类型：
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作者：
ANDERSSON, T;MINERS, JO;BIRKETT, DJ
1研究了地西泮在人肝微粒体中的初级代谢，以研究其动力学并鉴定负责地西泮主要代谢产物替马西泮和N-去甲基地西泮形成的细胞色素P450（CYP）异构体。2两种代谢产物的形成动力学均为非典型，与底物活化的发生一致。使用等效于Hill方程的S形V-max模型拟合数据。sigmoidicity的程度是更大的替马西泮形成比N-去甲基地西泮形成，使去甲基地西泮：替马西泮形成的比例增加的底物（地西泮）浓度降低。3 α-萘啶酮激活这两个反应，但更大的影响替马西泮形成比N-去甲基地西泮形成。在存在25 μ M α-萘啶酮的情况下，两种途径的动力学均近似于Michaelis-Menten动力学。4使用一系列α-萘啶酮亚型选择性抑制剂和抑制性抗CYP 2C抗体进行的研究表明，替马西泮的形成主要由CYP 3A亚型进行，而N-去甲基地西泮的形成由CYP 3A亚型和S-美芬妥英羟化酶介导。
1 The primary metabolism of diazepam was studied in human liver microsomes in order to investigate the kinetics and to identify the cytochrome P450 (CYP) isoforms responsible for the formation of the main diazepam metabolites, temazepam and N-desmethyldiazepam.2 The formation kinetics of both metabolites were atypical and consistent with the occurrence of substrate activation. A sigmoid V-max model equivalent to the Hill equation was used to fit the data. The degree of sigmoidicity was greater for temazepam formation than for N-desmethyldiazepam formation, so that the ratio of desmethyldiazepam:temazepam formation increased as the substrate (diazepam) concentration decreased.3 alpha-Naphthoflavone activated both reactions but with a greater effect on temazepam formation than on N-desmethyldiazepam formation. In the presence of 25 mu M alpha-naphthoflavone the kinetics for both pathways were approximated by Michaelis-Menten kinetics.4 Studies with a series of CYP isoform selective inhibitors and with an inhibitory anti-CYP2C antibody indicated that temazepam formation was carried out mainly by CYP3A isoforms, whereas the formation of N-desmethyldiazepam was mediated by both CYP3A isoforms and S-mephenytoin hydroxylase.