Influence of ethanol on the metabolism of alprazolam
Influence of ethanol on the metabolism of alprazolam
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DOI：
10.1080/17425255.2018.1483338
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发表时间：
2018-01-01
影响因子：
4.3
通讯作者：
Rao, Yulan
中科院分区：
文献类型：
--
作者：
Huang, Zhibin;Xu, Zhiru;Rao, Yulan
背景：阿普唑仑是临床上常用的苯二氮卓类药物，当阿普唑仑与乙醇共服时，会增加行为的应激性和攻击性。研究设计和方法：通过阿普唑仑和乙醇同时给药的大鼠体内药代动力学研究，以及体外人肝微粒体阿普唑仑与乙醇相互作用的研究。结果：与阿普唑仑单独给药(2 mg/kg)相比，乙醇同时给药3g/kg时，阿普唑仑的Cmax增加。阿普唑仑与乙醇合用5、10、30、120min后，脑内阿普唑仑浓度分别增加39%、17%、105%和642%。分子对接结果表明，乙醇与阿普唑仑的SER119残基结合后，阿普唑仑与CYP3A4的构象发生了变化，这在乙醇与阿普唑仑的结合过程中起着关键作用。结论：乙醇可能通过抑制细胞色素P3A4的活性而增加阿普唑仑的毒性，但其他药代动力学过程也可能受到影响。乙醇可改变细胞色素P3A4的构象，影响阿普唑仑的结合。
Background: Alprazolam is a commonly used benzodiazepine in clinical practice, and when coingested with ethanol, alprazolam can increase behavioral irritability and aggression. However, the mechanism of its interaction with ethanol remains unknown.Research design and methods: The pharmacokinetics of alprazolam was studied in vivo in rat experiments involving the simultaneous administration of alprazolam and ethanol, and the interactions between ethanol and alprazolam were investigated in vitro in human liver microsomes. In silico molecular docking was applied to analyze the change in the CYP3A4-alprazolam-binding conformation when ethanol was coadministered with alprazolam.Results: Compared with alprazolam administered alone (2 mg/kg), the C-max of alprazolam increased when ethanol was simultaneously administered at 3 g/kg. The concentrations of alprazolam significantly increased by 39%, 17%, 105%, and 642% at 5, 10, 30, and 120 min intervals in the brain when coadministered with ethanol, respectively. Molecular docking results suggested that the conformation of CYP3A4 with alprazolam changed when ethanol was bound to the SER119 residue, which seems critical in the process of CYP3A4-alprazolam binding.Conclusions: Ethanol might increase the toxicity of alprazolam by inhibiting the activity of CYP3A4, although other pharmacokinetic processes may be affected. Ethanol could change the conformation of CYP3A4 and affect alprazolam binding.