Modeling of drug-drug interactions between omeprazole and erythromycin with cytochrome P450 3A4 in vitro assay

Koroleva P.I.1, Kuzikov A.V.2, Masamrekh R.A.2, Filimonov D.A.1, Dmitriev A.V.1, Zaviyalova M.G.1, Rikova S.M.3, Shich E.V.3, Makhova A.A.3, Bulko T.V.1, Gilep A.A.4, Shumyantseva V.V.2

1. Institute of Biomedical Chemistry, Moscow, Russia
2. Institute of Biomedical Chemistry, Moscow, Russia; Pirogov Russian National Research Medical University (RNRMU), Moscow, Russia
3. Sechenov First Moscow Medical State University (Sechenov University), Moscow, Russia
4. Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus, Minsk, Belarus
Section: Experimental Study
DOI: 10.18097/PBMC20206603241      PubMed Id: 32588830
Year: 2020  Volume: 66  Issue: 3  Pages: 241-249
In the present study the electrochemical system based on recombinant cytochrome P450 3A4 (CYP3A4) was used for the investigation of potential drug-drug interaction between medicinal preparations employed for Helicobacter pylori eradication therapy. Drug interactions were demonstrated in association of omeprazole as a proton pump inhibitor (PPI) and macrolide antibiotic erythromycin during cytochrome P450 3A4-mediated metabolism. It was shown that in the presence of omeprazole the rate of N-demethylase activity of CYP3A4 to erythromycin measured by means of product (formaldehyde) formation decreased. Mass-spectrometry analysis of omeprazole sulfone as a CYP3A4-mediated metabolite demonstrated the absence of erythromycin influence on CYP3A4-dependent omeprazole metabolism. This phenomenon may be explained by lower spectral dissociation constant of CYP3A4-omeprazole complex (Kd = 18±2 μM) than that of CYP3A4-erythromycin complex (Kd = 52 μM). Using the electrochemical model of electrochemically-driven drug metabolism it is possible to register CYP3A4-mediated catalytic conversion of certain drugs. In vitro experiments of potential CYP3A4-mediated drug-drug interactions are in accordance with in silico modeling with program PASS and PoSMNA descriptors in the case of omeprazole/erythromycin combinations.
Download PDF:  
Keywords: cytochrome P450 3A4, drug-drug interactions, electrochemical analysis, omeprazole, erythromycin, mass-spectrometry

Koroleva, P. I., Kuzikov, A. V., Masamrekh, R. A., Filimonov, D. A., Dmitriev, A. V., Zaviyalova, M. G., Rikova, S. M., Shich, E. V., Makhova, A. A., Bulko, T. V., Gilep, A. A., Shumyantseva, V. V. (2020). Modeling of drug-drug interactions between omeprazole and erythromycin with cytochrome P450 3A4 in vitro assay. Biomeditsinskaya Khimiya, 66(3), 241-249.
This paper is also available as the English translation: 10.1134/S1990750821010030
 2024 (vol 70)
 2023 (vol 69)
 2022 (vol 68)
 2021 (vol 67)
 2020 (vol 66)
 2019 (vol 65)
 2018 (vol 64)
 2017 (vol 63)
 2016 (vol 62)
 2015 (vol 61)
 2014 (vol 60)
 2013 (vol 59)
 2012 (vol 58)
 2011 (vol 57)
 2010 (vol 56)
 2009 (vol 55)
 2008 (vol 54)
 2007 (vol 53)
 2006 (vol 52)
 2005 (vol 51)
 2004 (vol 50)
 2003 (vol 49)