title: Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of 186Re-MAG3-conjugated bisphosphonate (186Re-MAG3-HBP), an agent for treatment of painful bone metastases.
abstract: OBJECTIVE
  We have developed a (186)Re-mercaptoacetylglycylglycylglycine complex-conjugated bisphosphonate ((186)Re-MAG3-HBP) for the treatment of painful bone metastases. We assumed competitive inhibitors of protein binding to be useful for procuring a favorable biodistribution of (186)Re-MAG3-HBP for the palliation of bone pain because it has been reported that the concurrent administration of (99m)Tc-MAG3 and drugs with high affinity for serum protein produced competitive displacement at specific binding sites and enhanced total clearance and tissue distribution.
  
  
  METHODS
  The displacement effects of several protein-binding inhibitors on the protein binding of (186)Re-MAG3-HBP were investigated. Biodistribution experiments were performed by intravenously administering (186)Re-MAG3-HBP into rats with ceftriaxone as a competitive protein-binding inhibitor or saline.
  
  
  RESULTS
  The protein binding of (186)Re-MAG3-HBP in rat serum, human serum, and a human serum albumin solution was significantly decreased by the addition of ceftriaxone, which has high affinity for binding site I on serum albumin. In the biodistribution experiments, pretreatment with ceftriaxone enhanced the clearance of the radioactivity of (186)Re-MAG3-HBP in blood and nontarget tissues but had no effect on accumulation in bone.
  
  
  CONCLUSIONS
  The findings suggested that the use of protein-binding competitive inhibitors would be effective in improving the pharmacokinetics of radiopharmaceuticals with high affinity for serum protein.
authors: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors: Kazuma
authors: K
authors: Ogawa
authors: Takahiro
authors: T
authors: Mukai
authors: Keiichi
authors: K
authors: Kawai
authors: Norito
authors: N
authors: Takamura
authors: Hirofumi
authors: H
authors: Hanaoka
authors: Kazuyuki
authors: K
authors: Hashimoto
authors: Kazuhiro
authors: K
authors: Shiba
authors: Hirofumi
authors: H
authors: Mori
authors: Hideo
authors: H
authors: Saji
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001859:Bone Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000556:secondary; D004164:Diphosphonates / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009942:Organometallic Compounds / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010146:Pain / Q000150:complications* / Q000188:drug therapy*; D011485:Protein Binding / Q000187:drug effects; D011874:Radiometry; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012709:Serum Albumin / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: C517422:(((((4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl)carbamoylmethyl)carbamoylmethyl)carbamoylmethanethiolate)oxorhenium(V); D004164:Diphosphonates; D009942:Organometallic Compounds; D012709:Serum Albumin