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
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
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DOI：
10.1007/s00259-008-0925-8
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发表时间：
2009-01-01
影响因子：
9.1
通讯作者：
Saji, Hideo
中科院分区：
文献类型：
--
作者：
Ogawa, Kazuma;Mukai, Takahiro;Saji, Hideo
目的研制Re-186-MAG 3-HBP（186-mercaptoacetylglycylglycylglycine complex-conjugated bisphosphonate，Re-186-MAG 3-HBP）治疗骨转移癌疼痛。我们假设蛋白结合的竞争性抑制剂对于获得Re-186-MAG 3-HBP的良好生物分布以缓解骨痛是有用的，因为已经报道了同时施用Tc-99 m-MAG 3和对血清蛋白具有高亲和力的药物在特异性结合位点产生竞争性置换，并增强总清除率和组织分布。研究了结合抑制剂对Re-186-MAG 3-HBP蛋白结合的影响。结果在大鼠血清、人血清和人血清白蛋白溶液中加入对血清白蛋白结合位点I具有高亲和力的头孢曲松后，Re-186-MAG 3-HBP的蛋白结合率显著降低。在生物分布实验中，头孢曲松预处理增强了Re-186-MAG 3-HBP在血液和非靶组织中的放射性清除，但对骨中的蓄积没有影响。结论研究结果表明，使用蛋白结合竞争性抑制剂将有效地改善对血清蛋白具有高亲和力的放射性药物的药代动力学。
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.