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.
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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.
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