Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of Re-186-MAG3-conjugated bisphosphonate (Re-186-MAG3-HBP), an agent for treatment of painful bone metastases

Purpose We have developed a Re-186-mercaptoacetylglycylglycylglycine complex-conjugated bisphosphonate (Re-186-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 Re-186-MAG3-HBP for the palliation of bone pain because it has been reported that the concurrent administration of Tc-99m-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 Re-186-MAG3-HBP were investigated. Biodistribution experiments were performed by intravenously administering Re-186-MAG3-HBP into rats with ceftriaxone as a competitive protein-binding inhibitor or saline. Results The protein binding of Re-186-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 Re-186-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.