Attia Tamer Z, Yamashita Taku, Tsujino Hirofumi, Derayea Sayed M, Tsutsumi Yasuo, Uno Tadayuki
Graduate School of Pharmaceutical Sciences, Osaka University.
Analytical Chemistry Department, Faculty of Pharmacy, Minia University.
Chem Pharm Bull (Tokyo). 2019;67(8):810-815. doi: 10.1248/cpb.c19-00084.
Helicobacter pylori (H. pylori) infection is common and can result in gastric and duodenal ulcers, and in some cases, gastric lymphoma and cancer. Omeprazole (OMP)-in combination with clarithromycin (CLR), amoxicillin (AMX), tinidazole (TND), or metronidazole (MET)-is used in double or triple combination therapy for eradication of H. pylori. However, the roles of the drugs other than OMP are not clearly understood. Therefore, in the present study, we aimed to investigate any effects of these drugs on OMP metabolism by wild-type CYP2C19 using spectroscopy and enzyme kinetics. The dissociation constants (K) for CYP2C19 with OMP, CLR, AMX, TND, and MET were 8.6, 126, 156, 174, and 249 µM, respectively. The intrinsic clearance of OMP was determined to be 355 mL/min/µmol of CYP2C19. Metabolism of OMP was significantly inhibited by 69, 66, 28, and 40% in the presence of CLR, TND, AMX, and MET, respectively. Moreover, the combination of CLR and TND resulted in 76% inhibition of OMP metabolism, while the combination of AMX and MET resulted in 48% inhibition of OMP metabolism. Both combinations of drugs not only have antibacterial effects, but also enhance the effect of OMP by inhibiting its metabolism by CYP2C19. These results indicate that drug-drug interactions of co-administered drugs can cause complex effects, providing a basis for OMP dose adjustment when used in combination therapy for H. pylori eradication.
幽门螺杆菌（H. pylori）感染很常见，可导致胃溃疡和十二指肠溃疡，在某些情况下还会引发胃淋巴瘤和胃癌。奥美拉唑（OMP）与克拉霉素（CLR）、阿莫西林（AMX）、替硝唑（TND）或甲硝唑（MET）联合使用，用于根除幽门螺杆菌的双联或三联联合治疗。然而，除OMP外其他药物的作用尚不清楚。因此，在本研究中，我们旨在通过光谱学和酶动力学研究这些药物对野生型CYP2C19介导的OMP代谢的任何影响。CYP2C19与OMP、CLR、AMX、TND和MET的解离常数（K）分别为8.6、126、156、174和249 μM。OMP的内在清除率确定为355 mL/min/μmol CYP2C19。在CLR、TND、AMX和MET存在的情况下，OMP的代谢分别受到69%、66%、28%和40%的显著抑制。此外，CLR和TND的组合导致OMP代谢受到76%的抑制，而AMX和MET的组合导致OMP代谢受到48%的抑制。两种药物组合不仅具有抗菌作用，还通过抑制CYP2C19对OMP的代谢来增强OMP的效果。这些结果表明，联合用药的药物相互作用可产生复杂的影响，为幽门螺杆菌根除联合治疗中OMP剂量调整提供了依据。
