Citation

Huang Z, Xu Z, Wang H, Zhao Z, Rao Y. Expert Opin. Drug. Metab. Toxicol. 2018; 14(6): 551-559.

Affiliation

a Department of Forensic Medicine , School of Basic Medical Sciences, Fudan University , Shanghai 200032 , China.

Copyright

(Copyright © 2018, Informa Healthcare)

DOI

10.1080/17425255.2018.1483338

PMID

29848078

Abstract

BACKGROUND: 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. RESEARCH DESIGN AND METHODS: 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.

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 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.

Language: en

Keywords

Alprazolam; CYP3A4; CYP450 system; Drug-drug interaction; Ethanol; Forensic toxicology