Volume 19, Issue 43, January - June, 2025

Propoxazepam drug-drug interaction, mediated by cytochrome 450 2d6 (preclinical in vitro data)

Mykola Golovenko¹, Iryna Valivodz², Anatoliy Reder³, Vitalii Larionov^4♦

¹Doctor of Biological Sciences, Head of Department of Biomedicine, A.V. Bogatsky Physical-Chemical Institute of National Academy of Sciences of Ukraine, 65080, 86 Lyustdorfs`ka road, Odesa, Ukraine
<sup>2</sup>PhD in Biological Sciences, Junior Researcher, Department of Biomedicine, A.V. Bogatsky Physical-Chemical Institute of National Academy of Sciences of Ukraine, 65080, 86 Lyustdorfs`ka road, Odesa, Ukraine
³PhD in Chemical Sciences, General Director, SLC “Interchem”, 65080, 86 Lyustdorfs`ka road, Odesa, Ukraine
<sup>4</sup>PhD in Biological Sciences, Senior Researcher; Head of Laboratory of Molecular Pharmacology and Medicine, Department of Biomedicine, A.V. Bogatsky Physical-Chemical Institute of National Academy of Sciences of Ukraine, 65080, 86 Lyustdorfs`ka road, Odesa, Ukraine

^♦Corresponding author
PhD in Biological Sciences, Senior Researcher; Head of Laboratory of Molecular Pharmacology and Medicine, Department of Biomedicine, A.V. Bogatsky Physical-Chemical Institute of National Academy of Sciences of Ukraine, 65080, 86 Lyustdorfs`ka road, Odesa, Ukraine

ABSTRACT

The relevance of this study is the need to study potential drug interactions of the new analgesic propoxazepam, which belongs to the benzodiazepine group. Benzodiazepines are widely used for their anxiolytic and analgesic properties, and understanding their metabolic interactions is critical for safe clinical use. This study aimed to examine the effect of propoxazepam on CYP2D6 enzyme activity in human liver microsomes, a key enzyme in the metabolism of various drugs. The impact of propoxazepam on the 1-hydroxylation of bufuralol was analyzed using in vitro methods with human liver microsomes. This study involved adding propoxazepam at varying concentrations (0 to 100 μM) to the microsomal preparations along with the substrate and cofactors, specifically NADPH. It was established that propoxazepam consistently inhibited CYP2D6 activity, with the "concentrationactivity dependence" for both reversible and metabolism-dependent inhibition being similar: 67.5 ± 4.2 μM for reversible inhibition and 73.8 ± 3.3 μM for metabolismdependent inhibition. In addition, pharmacokinetic data showed that the predicted maximum unbound plasma propoxazepam concentration that could lead to significant interactions is ≥0.675 μM (approximately 0.275 μg/mL). Importantly, this concentration would not be reached after a single oral dose, suggesting that significant inhibition of CYP2D6 is unlikely in a clinical setting. The practical value of this work lies in the potential use of the findings by healthcare professionals and pharmacists to assess the safety of propoxazepam application in clinical practice, ultimately aiding in better management of patient therapies involving multiple medications.

Keywords: Propoxazepam, bufuralol, quinidine, paroxetine, reversible inhibition, metabolism dependent inhibition

Drug Discovery, 2025, 19(43), e5dd2047

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DOI: https://doi.org/10.54905/disssi.v19i43.e5dd2047

Published: 27 February 2025