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.Na osnove rekombinantnogo tsitokhroma R450 3A4 razrabotana sistema élektroanaliza dlia issledovaniia mezhlekarstvennykh vzaimodeĭstviĭ preparatov, primeniaemykh v kompleksnoĭ terapii pri lechenii zabolevaniĭ ZhKT, obuslovlennykh infitsirovaniem Helicobacter pylori. Pokazano mezhlekarstvennoe vzaimodeĭstvie ingibitora protonnogo nasosa omeprazola i makrolidnogo bakteriostaticheskogo antibiotika éritromitsina na urovne tsitokhroma R450 3A4. Vzaimnoe vliianie étikh lekarstvennykh sredstv na tsitokhrom R450 3A4 vyrazhaetsia v snizhenii skorosti reaktsii N-demetilirovaniia éritromitsina (registriruemoĭ po obrazovaniiu nizkomolekuliarnogo produkta formal'degida) v prisutstvii omeprazola; pri étom éritromitsin ne vliial na metabolicheskie prevrashcheniia omeprazola, registriruemye metodom mass-spektrometrii po obrazovaniiu produkta — omeprazol sul'fona. Takie mezhlekarstvennye vzaimodeĭstviia mogut byt' sviazany s bolee vysokim srodstvom omeprazola k tsitokhromu R450 3A4 (spektral'naia konstanta dissotsiatsii Kd = 18±2 mkM) po sravneniiu s éritromitsinom (Kd = 52 mkM). Razrabotannaia model'naia sistema pozvoliaet analizirovat' mezhlekarstvennye vzaimodeĭstviia na urovne tsitokhroma R450 3A4. Rezul'taty, poluchennye v éksperimentakh in vitro, polnost'iu soglasuiutsia s rezul'tatami in silico modelirovaniia, proizvedennogo s ispol'zovaniem programmy PASS i deskriptorov PoSMNA, kotoroe takzhe pokazalo vozmozhnost' mezhlekarstvennogo vzaimodeĭstviia omeprazola i éritromitsina na urovne biotransformatsii, osushchestvliaemoĭ tsitokhromom R450 3A4.