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Combined contributions of cytochrome P450s (CYPs) and non-enzymatic metabolism in the in vitro biotransformation of anaprazole, a novel proton pump inhibitor

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Abstract

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.

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Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Author notes

  1. Fei Liu, Yanjun Xu contributed equally to this work.

Authors and Affiliations

  1. Xuanzhu Biopharmaceutical Co., Ltd, Shijiazhuang, 051430, China

    Fei Liu, Yanjun Xu, Li Wang, Xifeng Ma & Zhen Zhang

  2. Beijing Institute of Pharmacology and Toxicology, No.27 Taiping Road, Haidian District, Beijing, 100850, China

    Xiaomei Zhuang

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  1. Fei Liu
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  2. Yanjun Xu
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  3. Li Wang
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  4. Xifeng Ma
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  5. Zhen Zhang
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  6. Xiaomei Zhuang
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Contributions

Conceptualization: Fei Liu, Yanjun Xu, and Xiaomei Zhuang; methodology and data analysis: Fei Liu, Li Wang, Zhen Zhang, and Xifeng Ma; writing—original draft preparation: Fei Liu; writing—review and editing: Xiaomei Zhuang. All authors have read and agreed to the published version of the manuscript. The authors confirm that all data were generated in-house and that no paper mill was used.

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Correspondence to Xiaomei Zhuang.

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Liu, F., Xu, Y., Wang, L. et al. Combined contributions of cytochrome P450s (CYPs) and non-enzymatic metabolism in the in vitro biotransformation of anaprazole, a novel proton pump inhibitor. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1759–1771 (2023). https://doi.org/10.1007/s00210-023-02415-7

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