Trospium Chloride Transport by Mouse Drug Carriers of the Slc22 and Slc47 Families.
Animals
Benzilates
/ metabolism
Biological Transport
Catecholamine Plasma Membrane Transport Proteins
/ genetics
HEK293 Cells
Humans
Kinetics
Mice, Inbred C57BL
Mice, Knockout
Muscarinic Antagonists
/ metabolism
Nortropanes
/ metabolism
Organic Cation Transport Proteins
/ genetics
Organic Cation Transporter 2
/ genetics
MATE
OCT
drug excretion
drug transport
transport
trospium
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
22 Dec 2020
22 Dec 2020
Historique:
received:
02
12
2020
revised:
17
12
2020
accepted:
18
12
2020
entrez:
30
12
2020
pubmed:
31
12
2020
medline:
30
3
2021
Statut:
epublish
Résumé
The muscarinic receptor antagonist trospium chloride (TCl) is used for pharmacotherapy of the overactive bladder syndrome. TCl is a hydrophilic positively charged drug. Therefore, it has low permeability through biomembranes and requires drug transporters for distribution and excretion. In humans, the organic cation transporters OCT1 and OCT2 and the multidrug and toxin extrusion MATE1 and MATE2-K carriers showed TCl transport. However, their individual role for distribution and excretion of TCl is unclear. Knockout mouse models lacking mOct1/mOct2 or mMate1 might help to clarify their role for the overall pharmacokinetics of TCl. In preparation of such experiments, TCl transport was analyzed in HEK293 cells stably transfected with the mouse carriers mOct1, mOct2, mMate1, and mMate2, respectively. Mouse mOct1, mOct2, and mMate1 showed significant TCl transport with Km values of 58.7, 78.5, and 29.3 µM, respectively. In contrast, mMate2 did not transport TCl but showed MPP TCl transport behavior as well as expression pattern were quite similar for the mouse carriers mOct1, mOct2, and mMate1 compared to their human counterparts.
Sections du résumé
BACKGROUND
BACKGROUND
The muscarinic receptor antagonist trospium chloride (TCl) is used for pharmacotherapy of the overactive bladder syndrome. TCl is a hydrophilic positively charged drug. Therefore, it has low permeability through biomembranes and requires drug transporters for distribution and excretion. In humans, the organic cation transporters OCT1 and OCT2 and the multidrug and toxin extrusion MATE1 and MATE2-K carriers showed TCl transport. However, their individual role for distribution and excretion of TCl is unclear. Knockout mouse models lacking mOct1/mOct2 or mMate1 might help to clarify their role for the overall pharmacokinetics of TCl.
METHOD
METHODS
In preparation of such experiments, TCl transport was analyzed in HEK293 cells stably transfected with the mouse carriers mOct1, mOct2, mMate1, and mMate2, respectively.
RESULTS
RESULTS
Mouse mOct1, mOct2, and mMate1 showed significant TCl transport with Km values of 58.7, 78.5, and 29.3 µM, respectively. In contrast, mMate2 did not transport TCl but showed MPP
CONCLUSION
CONCLUSIONS
TCl transport behavior as well as expression pattern were quite similar for the mouse carriers mOct1, mOct2, and mMate1 compared to their human counterparts.
Identifiants
pubmed: 33375004
pii: ijms22010022
doi: 10.3390/ijms22010022
pmc: PMC7792585
pii:
doi:
Substances chimiques
Benzilates
0
Catecholamine Plasma Membrane Transport Proteins
0
MATE1 protein, mouse
0
Muscarinic Antagonists
0
Nortropanes
0
Organic Cation Transport Proteins
0
Organic Cation Transporter 2
0
Slc22a1 protein, mouse
0
Slc22a2 protein, mouse
0
trospium chloride
1E6682427E
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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