[Modeling of drug-drug interactions between omeprazole and erythromycin with cytochrome P450 3A4 in vitro assay]
- PMID: 32588830
- DOI: 10.18097/PBMC20206603241
[Modeling of drug-drug interactions between omeprazole and erythromycin with cytochrome P450 3A4 in vitro assay]
Abstract
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.
Keywords: cytochrome P450 3A4; drug-drug interactions; electrochemical analysis; erythromycin; mass-spectrometry; omeprazole.
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