Title: Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients
Authors: Colom, Helena ×
Lloberas, Núria
Andreu, Franc
Caldés, Ana
Torras, Joan
Oppenheimer, Federico
Sanchez-Plumed, Jaime
Gentil, Miguel A
Kuypers, Dirk
Brunet, Mercè
Ekberg, Henrik
Grinyó, Josep M #
Issue Date: Jun-2014
Publisher: Nature Pub. Group
Series Title: Kidney International vol:85 issue:6 pages:1434-43
Article number: 10.1038/ki.2013.517
Abstract: Several factors contribute to mycophenolic acid (MPA) between-patient variability. Here we characterize the metabolic pathways of MPA and quantify the effect of combining genetic polymorphism of multidrug-resistant-associated protein-2, demographics, biochemical covariates, co-medication (cyclosporine (CsA) vs. macrolides), and renal function on MPA, 7-O-MPA-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) disposition, in renal transplant recipients, after mycophenolate mofetil. Complete pharmacokinetic profiles from 56 patients (five occasions) were analyzed. Enterohepatic circulation was modeled by transport of MPAG to the absorption site. This transport significantly decreased with increasing CsA trough concentrations (CtroughCsA). MPAG and AcMPAG plasma clearances significantly decreased with renal function. No significant influence of multidrug-resistant-associated protein-2 C24T single-nucleotide polymorphism was found. The model adequately predicted the increase in MPAG/AcMPAG exposures in CsA and macrolide patients with decreased renal function. This resulted in higher MPA exposures in macrolide patients versus CsA patients, and increased MPA exposures with renal function from 25 to 10 ml/min, in macrolide patients, owing to enhanced MPAG enterohepatic circulation. Lower-percentage enterohepatic circulation occurred with higher CtroughCsA and renal function values. The lack of MPA protein-binding modeling did not permit evaluation of the impact of renal function and CtroughCsA on MPA exposures in CsA patients. Thus, dose tailoring of covariates is recommended for target MPA exposure.Kidney International advance online publication, 8 January 2014; doi:10.1038/ki.2013.517.
ISSN: 0085-2538
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Nephrology
× corresponding author
# (joint) last author

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