PMID- 36847804
OWN - NLM
STAT- MEDLINE
DCOM- 20230714
LR  - 20231016
IS  - 1432-1912 (Electronic)
IS  - 0028-1298 (Linking)
VI  - 396
IP  - 8
DP  - 2023 Aug
TI  - Combined contributions of cytochrome P450s (CYPs) and non-enzymatic metabolism in 
      the in vitro biotransformation of anaprazole, a novel proton pump inhibitor.
PG  - 1759-1771
LID - 10.1007/s00210-023-02415-7 [doi]
AB  - 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.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, 
      part of Springer Nature.
FAU - Liu, Fei
AU  - Liu F
AD  - Xuanzhu Biopharmaceutical Co., Ltd, Shijiazhuang, 051430, China.
FAU - Xu, Yanjun
AU  - Xu Y
AD  - Xuanzhu Biopharmaceutical Co., Ltd, Shijiazhuang, 051430, China.
FAU - Wang, Li
AU  - Wang L
AD  - Xuanzhu Biopharmaceutical Co., Ltd, Shijiazhuang, 051430, China.
FAU - Ma, Xifeng
AU  - Ma X
AD  - Xuanzhu Biopharmaceutical Co., Ltd, Shijiazhuang, 051430, China.
FAU - Zhang, Zhen
AU  - Zhang Z
AD  - Xuanzhu Biopharmaceutical Co., Ltd, Shijiazhuang, 051430, China.
FAU - Zhuang, Xiaomei
AU  - Zhuang X
AD  - Beijing Institute of Pharmacology and Toxicology, No.27 Taiping Road, Haidian 
      District, Beijing, 100850, China. xiaomeizhuang@163.com.
LA  - eng
PT  - Journal Article
DEP - 20230227
PL  - Germany
TA  - Naunyn Schmiedebergs Arch Pharmacol
JT  - Naunyn-Schmiedeberg's archives of pharmacology
JID - 0326264
RN  - 0 (Proton Pump Inhibitors)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - 0 (Sulfoxides)
RN  - 0 (Sulfones)
RN  - 0 (Sulfides)
SB  - IM
MH  - Humans
MH  - *Proton Pump Inhibitors/metabolism
MH  - Chromatography, Liquid
MH  - *Tandem Mass Spectrometry/methods
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - Biotransformation
MH  - Sulfoxides/metabolism/pharmacology
MH  - Sulfones
MH  - Sulfides
OTO - NOTNLM
OT  - Anaprazole
OT  - CYP
OT  - Human liver microsomes (HLM)
OT  - In vitro
OT  - Non-enzyme metabolism
EDAT- 2023/02/28 06:00
MHDA- 2023/07/14 13:06
CRDT- 2023/02/27 11:14
PHST- 2022/09/29 00:00 [received]
PHST- 2023/01/31 00:00 [accepted]
PHST- 2023/07/14 13:06 [medline]
PHST- 2023/02/28 06:00 [pubmed]
PHST- 2023/02/27 11:14 [entrez]
AID - 10.1007/s00210-023-02415-7 [pii]
AID - 10.1007/s00210-023-02415-7 [doi]
PST - ppublish
SO  - Naunyn Schmiedebergs Arch Pharmacol. 2023 Aug;396(8):1759-1771. doi: 
      10.1007/s00210-023-02415-7. Epub 2023 Feb 27.