Multidrug resistance-associated protein 4 (MRP4) controls ganciclovir intracellular accumulation and contributes to ganciclovir-induced neutropenia in renal transplant patients

[Display omitted] Ganciclovir (GCV) is the cornerstone of cytomegalovirus prevention and treatment in transplant patients. It is associated with problematic adverse hematological effects in this population of immunosuppressed patients, which may lead to dose reduction thus favoring resistance. GCV c...

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Published in:Pharmacological research 2016-09, Vol.111, p.501-508
Main Authors: Billat, Pierre-André, Ossman, Tahani, Saint-Marcoux, Franck, Essig, Marie, Rerolle, Jean-Philippe, Kamar, Nassim, Rostaing, Lionel, Kaminski, Hannah, Fabre, Gabin, Otyepka, Michal, Woillard, Jean-Baptiste, Marquet, Pierre, Trouillas, Patrick, Picard, Nicolas
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antiviral Agents - adverse effects
Antiviral Agents - pharmacokinetics
Antiviral Agents - therapeutic use
Cytomegalovirus
Cytomegalovirus Infections - prevention & control
Female
Ganciclovir
Ganciclovir - adverse effects
Ganciclovir - pharmacokinetics
HEK293 Cells
Humans
Jurkat Cells
Kidney Transplantation
Male
Membrane transporters
Middle Aged
Multidrug resistance-associated protein 4
Multidrug Resistance-Associated Proteins - genetics
Multidrug Resistance-Associated Proteins - metabolism
Neutropenia - chemically induced
Neutropenia - genetics
Neutropenia - metabolism
Pharmacogenetics
Polymorphism, Single Nucleotide
Transplantation
Young Adult
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Summary:[Display omitted] Ganciclovir (GCV) is the cornerstone of cytomegalovirus prevention and treatment in transplant patients. It is associated with problematic adverse hematological effects in this population of immunosuppressed patients, which may lead to dose reduction thus favoring resistance. GCV crosses the membranes of cells, is activated by phosphorylation, and then stops the replication of viral DNA. Its intracellular accumulation might favor host DNA polymerase inhibition, hence toxicity. Following this hypothesis, we investigated the association between a selected panel of membrane transporter polymorphisms and the evolution of neutrophil counts in n=174 renal transplant recipients. An independent population of n=96 renal transplants served as a replication and experiments using HEK293T-transfected cells were performed to validate the clinical findings. In both cohorts, we found a variant in ABCC4 (rs11568658) associated with decreased neutrophil counts following valganciclovir (GCV prodrug) administration (exploratory cohort: β±SD=⿿0.68±0.28, p=0.029; replication cohort: β±SD=⿿0.84±0.29, p=0.0078). MRP4-expressing cells showed decreased GCV accumulation as compared to negative control cells (transfected with an empty vector) (⿿61%; p
ISSN:1043-6618
1096-1186
DOI:10.1016/j.phrs.2016.07.012