的比较(S)美芬妥因氧化氯胍体外:几个CYP亚型的贡献。

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科勒JK,索莫吉AA,博赫纳F

的比较(S)美芬妥因氧化氯胍体外:几个CYP亚型的贡献。

Br中国新药杂志。1999年8月,48 (2):158 - 67。

PubMed ID

10417492 (在PubMed

]

文摘

目的:比较(S)的氧化代谢美芬妥因氯胍体外和确定的参与各种细胞色素P450亚型。方法:4 '的形成动力学-hydroxymephenytoin和cycloguanil在人类肝微粒体从10测定肝脏样本,生成和抑制进行了研究使用特定化学抑制剂和单克隆抗体针对特定的CYP450亚型。表示CYP450酶被用来描述进一步体外CYP同种型的贡献。肝脏是CYP2C19基因分型用PCR扩增基因组DNA限制性内切核酸酶消化紧随其后。结果:肝脏是野生型对CYP2C19,除了HLS # 5的基因型是CYP2C19 * 1 / CYP2C19 * 2。的公里,和克林特值的形成4 ' -hydroxymephenytoin (S)美芬妥因和形成cycloguanil氯胍范围从50.8到51.6,43 - 380 microm, 1.0 - -13.9和0.5 - -2.5 nmol mg-1 h, h - -38.9和20.2 - -273.8和2.7 microl mg-1,分别。有显著关联的Vmax值cycloguanil和4”-hydroxymephenytoin形成(r = 0.95, P = 0.0004)。Cycloguanil形成显著抑制了奥美拉唑(CYP2C19/3A) troleandomycin (CYP3A),二乙基二硫代氨基甲酸(CYP2E1/3A) furafylline (CYP1A2)和(S)美芬妥因。4 ' -Hydroxymephenytoin形成由奥美拉唑抑制明显,二乙基二硫代氨基甲酸,氯胍,furafylline,安定,troleandomycin,和sulphaphenazole (CYP2C9)。人类CYP2E1和CYP3A4单克隆抗体没有抑制cycloguanil的形成或4 ' -hydroxymephenytoin, cycloguanil是由表示CYP3A4和CYP2C19 supersomes。 However, only expressed CYP2C19 and CYP2C19 supersomes formed 4'-hydroxymephenytoin. CONCLUSIONS: The oxidative metabolism of (S)-mephenytoin and proguanil in vitro is catalysed by CYPs 2C19 and 1A2, with the significant association between Vmax values suggesting that the predominant enzymes involved in both reactions are similar. However the degree of selectively of both drugs for CYP isoforms needs further investigation, particularly the involvement of CYP3A4 in the metabolism of proguanil. We assert that proguanil may not be a suitable alternative to (S)-mephenytoin as a probe drug for the CYP2C19 genetic polymorphism.

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药物酶

药物	酶	类	生物	药理作用	行动
美芬妥因	细胞色素P450 1 a2	蛋白质	人类	未知的	底物	细节