Combined contributions of cytochrome P450s (CYPs) and non-enzymatic metabolism in the in vitro biotransformation of anaprazole, a novel proton pump inhibitor.
Anaprazole
CYP
Human liver microsomes (HLM)
In vitro
Non-enzyme metabolism
Journal
Naunyn-Schmiedeberg's archives of pharmacology
ISSN: 1432-1912
Titre abrégé: Naunyn Schmiedebergs Arch Pharmacol
Pays: Germany
ID NLM: 0326264
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
29
09
2022
accepted:
31
01
2023
medline:
14
7
2023
pubmed:
28
2
2023
entrez:
27
2
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36847804
doi: 10.1007/s00210-023-02415-7
pii: 10.1007/s00210-023-02415-7
doi:
Substances chimiques
Proton Pump Inhibitors
0
Cytochrome P-450 Enzyme System
9035-51-2
Sulfoxides
0
Sulfones
0
Sulfides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1759-1771Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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