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

摘要: Ganciclovir (GCV) is the cornerstone of cytomegalovirus prevention and treatment in transplant patients. It associated with problematic adverse hematological effects this population immunosuppressed patients, which may lead to dose reduction thus favoring resistance. GCV crosses membranes cells, activated by phosphorylation, then stops replication viral DNA. Its intracellular accumulation might favor host DNA polymerase inhibition, hence toxicity. Following hypothesis, we investigated association between a selected panel membrane transporter polymorphisms evolution neutrophil counts n=174 renal recipients. An independent n=96 transplants served as experiments using HEK293T-transfected cells were performed validate clinical findings. In both cohorts, found variant ABCC4 (rs11568658) decreased following valganciclovir (GCV prodrug) administration (exploratory cohort: β±SD=-0.68±0.28, p=0.029; β±SD=-0.84±0.29, p=0.0078). MRP4-expressing showed compared negative control (transfected an empty vector) (-61%; p<0.0001). The efflux process was almost abolished expressing MRP4 rs11568658 protein. Molecular dynamic simulations crossing preferred location drug just beneath polar head group region, supports its interaction transporters.