Influence of ethanol on the metabolism of alprazolam.

Research paper by Zhibin Z Huang, Zhiru Z Xu, Hao H Wang, Ziqin Z Zhao, Yulan Y Rao

Indexed on: 01 Jun '18Published on: 01 Jun '18Published in: Expert opinion on drug metabolism & toxicology


Alprazolam is one of the most commonly used benzodiazepines 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. The pharmacokinetics of alprazolam were 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. Compared with alprazolam administered alone (2 mg/kg), the C of alprazolam increased when ethanol was simultaneously administered at 3 g/kg. The concentrations of alprazolam significantly increased 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. 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.