典型和非典型抗精神病对咖啡因的影响在大鼠肝微粒体氧化。

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丹尼尔佤邦,科特M, Wojcikowski J

典型和非典型抗精神病对咖啡因的影响在大鼠肝微粒体氧化。

波尔J杂志。2003;11 - 12月55 (6):1055 - 61。

PubMed ID

14730101 (在PubMed

]

文摘

咖啡因是一种标记CYP1A2活性的药物测试(3-N-demethylation)在人类和老鼠。此外,CYP3A似乎必不可少的新陈代谢(8-hydroxylation)。在其它的情况下,特别是7-N-demethylation的咖啡因,除了CYP1A2,其他CYP同功酶发挥相当大的作用,可能CYP2B和/或CYP2E1。本研究的目的是调查的影响两个经典精神安定剂(丙嗪、氟哌啶醇)和两个典型的(利培酮和sertindole)对细胞色素p - 450活动以咖啡因在大鼠肝微粒体氧化。结果表明,丙嗪,吩噻嗪安定与最简单的化学结构,显著地抑制其它——和3-N-demethylation 8-hydroxylation通过竞争或混合机制的咖啡因(microM Ki = 21.8、25.4和58.2,分别)。这表明抑制CYP1A2的丙嗪(抑制3 n -和1-N-demethylation),并可能CYP3A2 8-hydroxylation(抑制),但没有其他的CYP同功酶参与7-N-demethylation的咖啡因(例如CYP2B2和/或CYP2E1)。与丙嗪、氟哌啶醇的氧化反应没有影响咖啡因应用体外代谢模型。咖啡因抑制氧化的能力比丙嗪利培酮和sertindole像,而氟哌啶醇。利培酮似乎是非常弱的抑制剂3-N-demethylation和8-hydroxylation (Ki = 202.5 microM)和其它没有影响,7-N-demethylation的咖啡因。Sertindole是一个非常可怜的其它抑制剂——和7-N-demethylations 8-hydroxylation通路的标记物质(microM Ki = 132.1、434.1和173.3,分别); even the observed in vitro inhibition of 3-N-demethylation of caffeine by sertindole (Ki = 68.9 microM) cannot be of practical significance in vivo, considering extremely low pharmacological and therapeutic doses of the neuroleptic. In summary, among the investigated neuroleptics, only promazine showed significant inhibitory activity towards caffeine metabolism in vitro (inhibition of CYP1A2 and possibly CYP3A), which may be of pharmacological and clinical importance in vivo. In contrast to promazine, haloperidol and the investigated atypical neuroleptics had no or very weak effect on caffeine oxidation in vitro,of no in vivo significance. Considering the results of the present and previous studies, it seems highly likely that promazine may cause pharmacokinetic interactions, while atypical neuroleptics seem to be safe in this respect. Moreover, the observed reaction-dependent effects of promazine and sertindole provide indirect evidence that CYP1A2 is not the only isoenzyme important for the metabolism of caffeine, which requires further pharmacological and clinical consideration.

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药物酶

药物	酶	类	生物	药理作用	行动
丙嗪	细胞色素P450 1 a2	蛋白质	人类	未知的	底物 抑制剂	细节