Speaker
Description
Background: Increasing research suggests that the gut microbiota serves as a critical metabolic barrier for oral drug absorption. This study aims to investigate whether the commonly used clinical drugs proton pump inhibitors (PPIs) undergo metabolism within the gut microbiota.
Methods: Two representative PPIs, omeprazole (OME) and pantoprazole (PAN), was investigated using an in vitro intestinal bacterial incubation system. LCMS-9050 qTOF was employed to detect characteristic metabolites.
Results: Both OME and PAN underwent significant microbiota-mediated metabolism. Residual drug levels were 11.44% for OME vs. 83.97% for the sterilized group, and PAN retained 7.22% vs. 57.49% in the sterile group after 3 hours (p<0.0001). LC-MS/MS spectrometry identified OME metabolite M1 [C17H20N3O2S]+ at m/z 330.1. The MS2 fragment [C8H9N2O]+ m/z 149.0 and [C8H10NO]+ m/z 136.1 indicating deoxygenation at the sulphoxide site to form omeprazole sulfide. M1 peaked at 3 hours and then steadily declined. M1 undergoes metabolism to generate -14Da product M2 4-hydroxy omeprazole sulfide [C16H18N3O2S]+ m/z 316.1, peaking around 6 hours and maintaining constant levels thereafter. MS2 fragment [C8H9N2O]+ m/z 149.0 indicates demethylation occurred at the pyridine ring. Simultaneously, the sulfur-cleavage product M3 [C8H9N2OS]+ m/z 181.0 was detected, corresponding to 5-methoxy-2-mercaptobenzimidazole. Finally, the formation of M1, M2, and M3 structures was confirmed using reference standards. For PAN, similar to OME, -16Da sulfide product, -30Da demethylated sulfide products, and mercaptobenzimidazole product were also detected. All metabolites were also detected in mice model.
Conclusion: PPIs represented by omeprazole, undergo significant metabolism by gut microbiota. This process may potentially impact their therapeutic efficacy and safety.
