酶的动力学特征和识别负责adinazolam和N-desmethyladinazolam肝生物转化的男人。

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Venkatakrishnan K,冯·Moltke LL段SX, Fleishaker JC,材质RI,格林布拉特DJ

酶的动力学特征和识别负责adinazolam和N-desmethyladinazolam肝生物转化的男人。

50 J制药药物杂志。1998年3月,(3):265 - 74。

PubMed ID

9600717 (在PubMed

]

文摘

去甲基化的动力学的adinazolam N-desmethyladinazolam (NDMAD)和NDMAD didesmethyladinazolam (DDMAD),研究了与人类肝微粒体使用范围10 - 1000 microM基质浓度。特定的细胞色素P450 (CYP)亚型介导的生物转化被确定使用含有特定的微粒体CYP同功酶表达人类lymphoblastoid细胞,重组和CYP isoform-selective化学抑制剂的使用。Adinazolam被人类肝脏微粒体NDMAD脱甲基,NDMAD是脱甲基DDMAD;底物浓度,公里,反应速度是50%的最大是92年和259年microM,分别。另一个还未确定身份的代谢物(U)也是由NDMAD (microM 498公里)。Adinazolam被cDNA-expressed脱甲基CYP 2 c19(39公里microM)和CYP 3 a4 (microM 83公里);没有检测到活动观察cyp 1 a2, 2 c9 2 d6 2 e1。酮康唑,一个相对具体的CYP 3 a4抑制剂,抑制反应;导致50%的最大抑制,浓度IC50, 0.15 microM和抑制常数,Ki, < 0.04 microM五六肝脏测试。Troleandomycin, CYP 3 a4的特定抑制剂,抑制adinazolam去的IC50 1.96 microM。 The CYP 2C19-inhibitor omeprazole resulted in only partial inhibition (IC50 21 microM) and sulphaphenazole, alpha-naphthoflavone, quinidine and diethyldithiocarbamate did not inhibit the reaction. NDMAD was demethylated by cDNA-expressed CYP 3A4 (Km 220 microM, Hill number A 1.21), CYP 2C19 (Km 187 microM, Hill number A 1.29) and CYP 2C9 (Km 1068 microM). Formation of U was catalysed by CYP 3A4 alone. Ketoconazole strongly inhibited NDMAD demethylation (IC50 0.14 microM) and formation of U (IC50 < 0.1 microM) whereas omeprazole and sulphaphenazole had no effect on reaction rates. These results show that CYP 3A4 is the primary hepatic CYP isoform mediating the N-demethylation of adinazolam and NDMAD. Co-administration of adinazolam with CYP 3A4 inhibitors such as ketoconazole or erythromycin might lead to reduced efficacy, since adinazolam by itself has relatively weak benzodiazepine agonist activity, with much of the pharmacological activity of adinazolam being attributable to its active metabolite NDMAD.

DrugBank数据引用了这篇文章

药物酶

药物	酶	类	生物	药理作用	行动
Adinazolam	细胞色素P450 2 c19	蛋白质	人类	未知的	底物	细节
Adinazolam	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节