Pharmacogenetic-Whole blood and intracellular pharmacokinetic-Pharmacodynamic

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both comp...

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Published in:PloS one 2020-03, Vol.15 (3), p.e0230195
Main Authors: Tron, Camille, Woillard, Jean-Baptiste, Houssel-Debry, Pauline, David, Véronique, Jezequel, Caroline, Rayar, Michel, Balakirouchenane, David, Blanchet, Benoit, Debord, Jean, Petitcollin, Antoine, Roussel, Mickaël, Verdier, Marie-Clémence, Bellissant, Eric, Lemaitre, Florian
Format: Article
Language:English
Subjects:
Analysis
Biological markers
Cytochrome P-450
EDTA
Everolimus
Genetic polymorphisms
Genotypes
Immunotherapy
Liver transplantation
Organ transplant recipients
Organ transplantation
Precision medicine
Tacrolimus
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Summary:Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0230195