PMID- 34918875
OWN - NLM
STAT- MEDLINE
DCOM- 20220224
LR  - 20220325
IS  - 2052-1707 (Electronic)
IS  - 2052-1707 (Linking)
VI  - 10
IP  - 1
DP  - 2022 Feb
TI  - Metopimazine is primarily metabolized by a liver amidase in humans.
PG  - e00903
LID - 10.1002/prp2.903 [doi]
LID - e00903
AB  - Metopimazine (MPZ) is a peripherally restricted, dopamine D2 receptor antagonist 
      used for four decades to treat acute nausea and vomiting. MPZ is currently under 
      clinical investigation for the treatment of gastroparesis (GP). MPZ undergoes 
      high first-pass metabolism that produces metopimazine acid (MPZA), the major 
      circulating metabolite in humans. Despite a long history of use, the enzymes 
      involved in the metabolism of MPZ have not been identified. Here we report a 
      series of studies designed to identify potential MPZ metabolites in vitro, 
      determine their clinical relevance in humans, and elucidate the enzymes 
      responsible for their formation. The findings demonstrated that the formation of 
      MPZA was primarily catalyzed by human liver microsomal amidase. Additionally, 
      human liver cytosolic aldehyde oxidase (AO) catalyzes the formation of MPZA, in 
      vitro, although to a much lesser extent. Neither cytochrome P450 enzymes nor 
      flavin-monooxygenases (FMO) were involved in the formation MPZA, although two 
      minor oxidative pathways were catalyzed by CYP3A4 and CYP2D6 in vitro. Analysis 
      of plasma samples from subjects dosed 60 mg of MPZ verified that these oxidative 
      pathways are very minor and that CYP enzyme involvement was negligible compared 
      to microsomal amidase/hydrolase in overall MPZ metabolism in humans. The 
      metabolism by liver amidase, an enzyme family not well defined in small molecule 
      drug metabolism, with minimal metabolism by CYPs, differentiates this drug from 
      current D2 antagonists used or in development for the treatment of GP.
CI  - (c) 2021 Neurogastrx Inc. Pharmacology Research & Perspectives published by British 
      Pharmacological Society and American Society for Pharmacology and Experimental 
      Therapeutics and John Wiley & Sons Ltd.
FAU - Busby, Robert W
AU  - Busby RW
AUID- ORCID: 0000-0001-6694-1207
AD  - Neurogastrx, Inc., Woburn, Massachusetts, USA.
FAU - Cai, Xiaokun
AU  - Cai X
AD  - QPS, Newark, Delaware, USA.
FAU - Yang, Sihyung
AU  - Yang S
AD  - QPS, Newark, Delaware, USA.
FAU - Ramos, Luis
AU  - Ramos L
AD  - QPS, Newark, Delaware, USA.
FAU - Venkatarangan, Lata
AU  - Venkatarangan L
AD  - QPS, Newark, Delaware, USA.
FAU - Shen, Helen
AU  - Shen H
AD  - QPS, Newark, Delaware, USA.
FAU - Wax, Stephen
AU  - Wax S
AD  - Neurogastrx, Inc., Woburn, Massachusetts, USA.
FAU - Sadeque, Abu J M
AU  - Sadeque AJM
AD  - QPS, Newark, Delaware, USA.
FAU - De Colle, Cyril
AU  - De Colle C
AD  - Neurogastrx, Inc., Woburn, Massachusetts, USA.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - United States
TA  - Pharmacol Res Perspect
JT  - Pharmacology research & perspectives
JID - 101626369
RN  - 0 (Antiemetics)
RN  - 0 (Dopamine D2 Receptor Antagonists)
RN  - 0 (Isonipecotic Acids)
RN  - 238S75V9AV (metopimazine)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 3.5.- (Amidohydrolases)
RN  - EC 3.5.1.4 (amidase)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Amidohydrolases/*metabolism
MH  - Animals
MH  - Antiemetics/metabolism
MH  - Cohort Studies
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - Dogs
MH  - Dopamine D2 Receptor Antagonists/*metabolism
MH  - Double-Blind Method
MH  - Female
MH  - Humans
MH  - Isonipecotic Acids/*metabolism
MH  - Male
MH  - Microsomes, Liver/enzymology/*metabolism
MH  - Middle Aged
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Young Adult
PMC - PMC8929364
OTO - NOTNLM
OT  - D2
OT  - D3
OT  - aldehyde oxidase
OT  - amidase
OT  - dopamine receptor agonists
OT  - drug metabolism
OT  - gastroparesis
OT  - metopimazine
OT  - metopimazine acid
EDAT- 2021/12/18 06:00
MHDA- 2022/02/25 06:00
PMCR- 2021/12/17
CRDT- 2021/12/17 08:48
PHST- 2021/10/08 00:00 [received]
PHST- 2021/11/18 00:00 [accepted]
PHST- 2021/12/17 08:48 [entrez]
PHST- 2021/12/18 06:00 [pubmed]
PHST- 2022/02/25 06:00 [medline]
PHST- 2021/12/17 00:00 [pmc-release]
AID - PRP2903 [pii]
AID - 10.1002/prp2.903 [doi]
PST - ppublish
SO  - Pharmacol Res Perspect. 2022 Feb;10(1):e00903. doi: 10.1002/prp2.903.