Xuanzhu Biopharmaceutical Co., Ltd, Shijiazhuang, 051430, China.
Beijing Institute of Pharmacology and Toxicology, No.27 Taiping Road, Haidian District, Beijing, 100850, China.
Naunyn Schmiedebergs Arch Pharmacol. 2023 Aug;396(8):1759-1771. doi: 10.1007/s00210-023-02415-7. Epub 2023 Feb 27.
Anaprazole, a new proton pump inhibitor (PPI), is designed for the treatment of acid-related diseases, such as gastric ulcers and gastroesophageal reflux. This study explored the in vitro metabolic transformation of anaprazole. The metabolic stabilities of anaprazole in human plasma and human liver microsomes (HLM) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Then, the contribution (%) of non-enzymatic and cytochrome P450s (CYPs) enzyme-mediated anaprazole metabolism was assessed. To obtain the metabolic pathways of anaprazole, the metabolites generated in HLM, thermal deactivated HLM, and cDNA-expressed recombinant CYPs incubation systems were identified by ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS). Results showed that anaprazole was very stable in human plasma and unstable in HLM. The contribution (%) of non-enzymatic vs. CYPs enzyme-mediated metabolism was 49% vs. 51%. CYP3A4 was the major enzyme (48.3%), followed by CYP2C9 (17.7%) and CYP2C8 (12.3%), in responsible for the metabolism of anaprazole. Specific chemical inhibitors targeting CYP enzymes notably blocked the metabolic transformation of anaprazole. Six metabolites of anaprazole were identified in the non-enzymatic system, whereas 17 metabolites were generated in HLM. The biotransformation reactions mainly included sulfoxide reduction to thioether, sulfoxide oxidation to sulfone, deoxidation, dehydrogenation, O-dealkylation or O-demethylation of thioether, O-demethylation and dehydrogenation of thioether, O-dealkylation and dehydrogenation of thioether, thioether O-dealkylation and dehydrogenation of thioether, and O-dealkylation of sulfone. Both enzymatic and non-enzymatic metabolisms contribute to the clearance of anaprazole in human. Anaprazole is less likely to develop drug-drug interactions in clinical use compared to other PPIs.
奥美拉唑是一种新型质子泵抑制剂（PPI），用于治疗胃酸相关疾病，如胃溃疡和胃食管反流。本研究探讨了奥美拉唑的体外代谢转化。采用液相色谱-串联质谱法（LC-MS/MS）分析奥美拉唑在人血浆和人肝微粒体（HLM）中的代谢稳定性。然后，评估非酶和细胞色素 P450（CYP）酶介导的奥美拉唑代谢的贡献（%）。为了获得奥美拉唑的代谢途径，通过超高效液相色谱/四极杆飞行时间质谱法（UPLC/Q-TOF-MS）鉴定在 HLM、热失活 HLM 和 cDNA 表达重组 CYP 孵育系统中生成的代谢物。结果表明，奥美拉唑在人血浆中非常稳定，在 HLM 中不稳定。非酶与 CYP 酶介导的代谢的贡献（%）分别为 49%和 51%。CYP3A4 是主要酶（48.3%），其次是 CYP2C9（17.7%）和 CYP2C8（12.3%），负责奥美拉唑的代谢。针对 CYP 酶的特异性化学抑制剂显著阻断了奥美拉唑的代谢转化。在非酶系统中鉴定出奥美拉唑的 6 种代谢物，而在 HLM 中生成 17 种代谢物。生物转化反应主要包括亚砜还原为硫醚、亚砜氧化为砜、脱氧化、脱氢、硫醚的 O-去烷基化或 O-去甲基化、硫醚的 O-去甲基化和脱氢、硫醚的 O-去烷基化和脱氢、硫醚的 O-去烷基化和脱氢、砜的 O-去烷基化。酶促和非酶促代谢均有助于人清除奥美拉唑。与其他 PPI 相比，奥美拉唑在临床应用中不太可能发生药物相互作用。
