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Document type
články
články
Document record
Source: BMČ - články
Title
MRP4 is responsible for the efflux transport of mycophenolic acid β-d glucuronide (MPAG) from hepatocytes to blood / J. Berthier, M. Benmameri, FL. Sauvage, G. Fabre, B. Chantemargue, H. Arnion, P. Marquet, P. Trouillas, N. Picard, F. Saint-Marcoux,
Author
Berthier, Joseph
INSERM, UMR 1248, Univ. Limoges, Limoges, France. CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France.

Benmameri, Mehdi
INSERM, UMR 1248, Univ. Limoges, Limoges, France.

Sauvage, François-Ludovic
INSERM, UMR 1248, Univ. Limoges, Limoges, France.

Fabre, Gabin
INSERM, UMR 1248, Univ. Limoges, Limoges, France.

Chantemargue, Benjamin
INSILIBIO, Limoges, France.

Arnion, Hélène
INSERM, UMR 1248, Univ. Limoges, Limoges, France.

Marquet, Pierre
INSERM, UMR 1248, Univ. Limoges, Limoges, France. CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France.

Trouillas, Patrick
INSERM, UMR 1248, Univ. Limoges, Limoges, France. RCPTM, Univ. Palacký of Olomouc, Olomouc, Czech Republic.

Picard, Nicolas
INSERM, UMR 1248, Univ. Limoges, Limoges, France. CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France.

Saint-Marcoux, Franck
INSERM, UMR 1248, Univ. Limoges, Limoges, France. CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France.

Cited source
Xenobiotica (London. Print). 2021, roč. 51, č. 1, s. 105-114. ISSN: 0049-8254; 1366-5928 (elektronická verze).
Date of issue
2021
Language
angličtina
Country
Spojené království
Document type
články
DOI
Pubmed ID
Link
Record number
bmc20027574
Persistent link
MESH descriptor
biologický transport
lidé
ledviny (metabolismus)
játra (metabolismus)
kyselina mykofenolová (analogy a deriváty, metabolismus)
glukuronidy (metabolismus)
hepatocyty (metabolismus)
membránové transportní proteiny (metabolismus)
proteiny spojené s mnohočetnou rezistencí k lékům (metabolismus)
molekulový docking
Genre
English Abstract
Mycophenolic acid (MPA) has become a cornerstone of immunosuppressive therapy, in particular for transplant patients. In the gastrointestinal tract, the liver and the kidney, MPA is mainly metabolized into phenyl-β-d glucuronide (MPAG). Knowledge about the interactions between MPA/MPAG and membrane transporters is still fragmented. The aim of the present study was to explore these interactions with the basolateral hepatic MRP4 transporter. The inhibition of the MRP4-driven transport by various drugs which can be concomitantly prescribed was also evaluated. In vitro experiments using vesicles overexpressing MRP4 showed an ATP-dependent transport of MPAG driven by MRP4 (Michaelis-Menten constant of 233.9 ± 32.8 µM). MPA was not effluxed by MRP4. MRP4-mediated transport of MPAG was inhibited (from -43% to -84%) by ibuprofen, cefazolin, cefotaxime and micafungin. An in silico approach based on molecular docking and molecular dynamics simulations rationalized the mode of binding of MPAG to MRP4. The presence of the glucuronide moiety in MPAG was highlighted as key, being prone to make electrostatic and H-bond interactions with specific residues of the MRP4 protein chamber. This explains why MPAG is a substrate of MRP4 whereas MPA is not.
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