Metabolic interaction between ethanol, high-dose alprazolam and its two main metabolites using human liver microsomes in vitro

Tanaka, Einosuke; Nakamura, Takako; Terada, Masaru; Shinozuka, Tatsuo; Honda, Katsuya

doi:10.1016/j.jflm.2006.11.004

« Previous Next »Journal of Forensic and Legal Medicine
Volume 14, Issue 6 , Pages 348-351, August 2007

Metabolic interaction between ethanol, high-dose alprazolam and its two main metabolites using human liver microsomes in vitro

Einosuke Tanaka
- Department of Legal Medicine, Institute of Community Medicine, University of Tsukuba, Ibaraki-ken 305-8575, Japan
- Corresponding author. Address: Department of Legal Medicine, Institute of Community Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki-ken 305-8575, Japan. Tel./fax: +81 29 853 3057.
Takako Nakamura
- Department of Legal Medicine, Institute of Community Medicine, University of Tsukuba, Ibaraki-ken 305-8575, Japan
Masaru Terada
- Department of Legal Medicine, School of Medicine, Toho University, 5-21-16 Omorinishi, Otaku, Tokyo 143-8540, Japan
Tatsuo Shinozuka
- Department of Legal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Katsuya Honda
- Department of Legal Medicine, Institute of Community Medicine, University of Tsukuba, Ibaraki-ken 305-8575, Japan

Received 17 April 2006; received in revised form 21 August 2006; accepted 17 November 2006.

Abstract

Alprazolam is widely used as a short-acting antidepressant and anxiolytic agent and its effect appears at very low doses while ethanol is used as a social drug worldwide. Sometimes, toxic interactions occur following combined administration of these two drugs. In this study we have investigated the interaction between ethanol and high-dose alprazolam using human liver microsomes in vitro.

The interaction effects between ethanol and alprazolam were examined by a mixed-function oxidation reaction using a human liver microsomal preparation. Alprazolam and its two main metabolites (α-hydroxyalprazolam: α-OH alprazolam, 4-hydroxyalprazolam: 4-OH alprazolam) were measured by HPLC/UV.

The production of 4-OH alprazolam, one main metabolite of alprazolam, was weakly inhibited by higher dose of ethanol, but not α-OH alprazolam.

These results using a human liver microsomal preparation show that the production of 4-OH alprazolam is weakly inhibited by ethanol but not α-OH alprazolam. Toxic levels may be reached by simultaneous administration of ethanol and high-dose alprazolam.

Keywords: Drug interaction, Cytochrome P450, Ethanol, Alprazolam, In vitro