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 K_d = 18 ± 2 µM) than that for erythromycin (K_d = 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.

中文翻译：

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奥美拉唑与红霉素在细胞色素P450依赖系统中的药物相互作用的体外建模

摘要

在本研究中，已开发了一种基于重组细胞色素P450 3A4（CYP3A4）的电化学系统，用于分析幽门螺杆菌处方药之间潜在的药物-药物相互作用根除疗法。证明了奥美拉唑（质子泵抑制剂； PPI）与细胞色素P450 3A4诱导的大环内酯类抗生素红霉素之间的药物相互作用。在存在奥美拉唑的情况下，通过反应产物（甲醛）的形成来衡量，通过CYP3A4进行的红霉素N-去甲基化速率降低，而红霉素对奥美拉唑的代谢没有影响，使用奥美拉唑砜作为代谢产物在代谢过程中形成的代谢产物进行了质谱分析CYP3A4依赖性代谢。CYP3A4对奥美拉唑的亲和力（光谱解离常数K _d = 18±2 µM）比对红霉素（K _d）的亲和力更高，可以解释这些药物之间的相互作用。= 52 µM）。使用开发的模型系统，可以分析由细胞色素P450 3A4诱导的药物相互作用。通过体外实验获得的结果与使用PASS程序和PoSMNA描述符进行的计算机模拟的结果非常吻合，这也表明了奥美拉唑和红霉素在通过细胞色素进行生物转化的水平上发生药物相互作用的可能性P450 3A4。