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

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.