Pharmacogenetic-Whole blood and intracellular pharmacokinetic-Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients.
ATP Binding Cassette Transporter, Subfamily B
/ genetics
Aged
Cytochrome P-450 CYP3A
/ genetics
Female
Genotype
Humans
Immunosuppression Therapy
/ methods
Immunosuppressive Agents
/ pharmacokinetics
Leukocytes, Mononuclear
/ metabolism
Liver Transplantation
/ methods
Male
Middle Aged
Pharmacogenetics
/ methods
Pharmacogenomic Testing
/ methods
Polymorphism, Single Nucleotide
/ genetics
Tacrolimus
/ pharmacokinetics
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
26
07
2019
accepted:
24
02
2020
entrez:
13
3
2020
pubmed:
13
3
2020
medline:
23
6
2020
Statut:
epublish
Résumé
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<0.05). No association was found between CYP3A4 or CYP3A5 genotypes and TAC whole blood or intracellular concentrations. Finally, intra-PBMC calcineurin activity appeared incompletely inhibited by TAC and less than 50% of patients were expected to achieve intracellular IC50 concentration (100 pg/millions of cells) at therapeutic whole blood concentration (i.e.: 4-10 ng/mL). Together, these data suggest that personalized medicine regarding TAC therapy might be optimized by ABCB1 pharmacogenetic biomarkers and by monitoring intracellular concentration whereas the relationship between intracellular TAC exposure and pharmacodynamics biomarkers more specific than calcineurin activity should be further investigated.
Identifiants
pubmed: 32163483
doi: 10.1371/journal.pone.0230195
pii: PONE-D-19-21120
pmc: PMC7067455
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily B
0
Immunosuppressive Agents
0
Cytochrome P-450 CYP3A
EC 1.14.14.1
Tacrolimus
WM0HAQ4WNM
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0230195Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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