Modeling of Drug-Drug Interactions between Omeprazole and Erythromycin in the Cytochrome P450-Dependent System In vitro

Abstract

Abstract: In the present study an electrochemical system based on recombinant cytochrome P450 3A4 (CYP3A4) has been developed for analysis of potential drug-drug interactions between drugs prescribed for Helicobacter pylori eradication therapy. The drug-drug interaction between omeprazole (a proton pump inhibitor; PPI) and macrolide antibiotic erythromycin induced by cytochrome P450 3A4 was demonstrated. In the presence of omeprazole, the rate of erythromycin N-demethylation by CYP3A4, measured by the reaction product (formaldehyde) formation, decreased, while erythromycin had no effect on omeprazole metabolism evaluated using mass-spectrometry analysis of omeprazole sulfone as a metabolite formed during CYP3A4-dependent metabolism. These drug-drug interactions may be explained by a higher affinity of CYP3A4 for omeprazole (the spectral dissociation constant Kd = 18 ± 2 µM) than that for erythromycin (Kd = 52 µM). Using the developed model system, it is possible to analyze drug-drug interactions induced by cytochrome P450 3A4. The results obtained by means of in vitro experiments well correspond to the results of in silico modeling performed using the PASS program and PoSMNA descriptors, which also showed the possibility of drug-drug interactions between omeprazole and erythromycin at the level of biotransformation carried out by cytochrome P450 3A4.