Influence of ethanol on the metabolism of alprazolam.

ABSTRACT

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.

KEYWORDS:

• Alprazolam
• CYP3A4
• CYP450 system
• drug–drug interaction
• ethanol
• forensic toxicology

Acknowledgments

Zhibin Huang especially wishes to thank Tianfang Yu, who has provided a lot of help on manuscript writing and revision.

Author contributions

Zhibin Huang and Zhiru Xu were equally contributed to this work. They performed all the experiments together. Hao Wang was involved in the analysis and interpretation of the data. Ziqin Zhao and Yulan Rao designed the research. All authors agree to be accountable for all aspects of the work.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have received an honorarium from Expert Opinion on Drug Metabolism and Toxicology for their review work, but have no other relevant financial relationships to disclose.

Supplementary material

Supplementary data can be accessed here

Additional information

Funding

This study was funded by the Open Project Program of the Department of Forensic Medicine, Fudan University [Fund: FY2015-6].