title: Dexmedetomidine does not interfere with meta-iodobenzylguanidine (MIBG) uptake at clinically relevant concentrations.
abstract: Neuroblastoma is a pediatric malignancy, and most tumor cells express the norepinephrine transporter (NET) enabling uptake of NET ligands. Meta-iodobenzylguanidine (MIBG) is a NET-specific ligand used as a highly specific imaging agent and targeted radiotherapeutic. Patients with neuroblastoma frequently require sedation during targeted radiotherapy. Dexmedetomidine has been increasingly used to achieve efficacious sedation. There are theoretical concerns that this highly selective alpha-2 adrenergic receptor agonist may interfere with active uptake of MIBG through the NET transporter. In this study, we analyzed the impact of [125-iodine]-labeled MIBG ([125I]MIBG) uptake in the presence of dexmedetomidine in human neuroblastoma-derived cellular models.
  
  
  
  Carrier-free [125I]MIBG was synthesized using UltraTrace® resin (Molecular Insight Pharmaceuticals, Inc., Tarrytown, NY) through radioiododestannylation from a tin precursor bound by a solid-state polymer. NET (SLC6A2) protein expression was determined in human neuroblastoma cell lines (BE2C, SKNSH and IMR5). [125I]MIBG internalization studies were performed using [125I]MIBG alone or in combination with either desipramine or dexmedetomidine. Dexmedetomidine and desipramine competitive inhibition studies were performed and concentration at 50% maximal inhibition was calculated. Finally, NET inhibitor dissociation studies were performed in which after pre-incubation with either desipramine or dexmedetomidine, cells were washed and [125I]MIBG was added.
  
  
  
  We show dose-dependent inhibition of [125I]MIBG uptake by dexmedetomidine, but at several logs lower potency than the known NET inhibitor desipramine. A review of pediatric dexmedetomidine pharmacokinetic data shows that the concentrations achieved in the serum are much lower than those required to block MIBG uptake.
  
  
  
  We conclude that dexmedetomidine will not interfere with therapeutic [131I]MIBG efficacy.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Vandana
authors.initials: V
authors.lastname: Batra
authors.affiliation: Division of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Mehran
authors.initials: M
authors.lastname: Makvandi
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Athena F
authors.initials: AF
authors.lastname: Zuppa
authors.affiliation: Department of Pharmacy Services, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Neil
authors.initials: N
authors.lastname: Patel
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Elias
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pryma
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
mesh_terms: D019797:3-Iodobenzylguanidine / Q000493:pharmacokinetics*; D020927:Dexmedetomidine / Q000493:pharmacokinetics*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D006993:Hypnotics and Sedatives; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D019797:3-Iodobenzylguanidine; D020927:Dexmedetomidine
keywords: MIBG; dexmedetomidine; drug-drug interactions; neuroblastoma