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

Overview

Journal Eur J Nucl Med Mol Imaging

Specialties Biophysics
Nuclear Medicine
Radiology

Date 2008 Aug 19

PMID 18709369

Citations 7

Authors

Kazuma Ogawa

Takahiro Mukai

Keiichi Kawai

Norito Takamura

Hirofumi Hanaoka

Kazuyuki Hashimoto

Kazuhiro Shiba

Hirofumi Mori

Hideo Saji

Affiliations

Soon will be listed here.

Abstract

Purpose: 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.

Citing Articles

Differences in the Renal Accumulation of Radiogallium-Labeled (Glu) Peptides Containing Different Optical Isomers of Glutamic Acid.

Ogawa K, Nishizawa K, Mishiro K, Munekane M, Fuchigami T, Echigo H Molecules. 2024; 29(17).

PMID: 39274840 PMC: 11396517. DOI: 10.3390/molecules29173993.

Optimizing the pharmacokinetics of an At-labeled RGD peptide with an albumin-binding moiety via the administration of an albumin-binding inhibitor.

Echigo H, Munekane M, Fuchigami T, Washiyama K, Mishiro K, Wakabayashi H Eur J Nucl Med Mol Imaging. 2024; 51(9):2663-2671.

PMID: 38570359 PMC: 11224111. DOI: 10.1007/s00259-024-06695-w.

Bisphosphonates as Radiopharmaceuticals: Spotlight on the Development and Clinical Use of DOTAZOL in Diagnostics and Palliative Radionuclide Therapy.

Souche C, Fouillet J, Rubira L, Donze C, Deshayes E, Fersing C Int J Mol Sci. 2024; 25(1).

PMID: 38203632 PMC: 10779041. DOI: 10.3390/ijms25010462.

Synthesis and evaluation of radiogallium-labeled long-chain fatty acid derivatives as myocardial metabolic imaging agents.

Effendi N, Mishiro K, Wakabayashi H, Gabryel-Skrodzka M, Shiba K, Taki J PLoS One. 2021; 16(12):e0261226.

PMID: 34910775 PMC: 8673672. DOI: 10.1371/journal.pone.0261226.

Evaluation of Ga-DOTA-(D-Asp) as bone imaging agents: D-aspartic acid peptides as carriers to bone.

Ogawa K, Ishizaki A, Takai K, Kitamura Y, Makino A, Kozaka T Sci Rep. 2017; 7(1):13971.

PMID: 29070853 PMC: 5656653. DOI: 10.1038/s41598-017-14149-7.

References

Ogawa K, Mukai T, Arano Y, Otaka A, Ueda M, Uehara T . Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation. Nucl Med Biol. 2006; 33(4):513-20. DOI: 10.1016/j.nucmedbio.2006.03.006. View

Patel I, Chen S, PARSONNET M, Hackman M, Brooks M, Konikoff J . Pharmacokinetics of ceftriaxone in humans. Antimicrob Agents Chemother. 1981; 20(5):634-41. PMC: 181765. DOI: 10.1128/AAC.20.5.634. View

Lewington V . Bone-seeking radionuclides for therapy. J Nucl Med. 2005; 46 Suppl 1:38S-47S. View

Neves M, Gano L, Pereira N, Costa M, Costa M, Chandia M . Synthesis, characterization and biodistribution of bisphosphonates Sm-153 complexes: correlation with molecular modeling interaction studies. Nucl Med Biol. 2002; 29(3):329-38. DOI: 10.1016/s0969-8051(01)00305-5. View

Seddon M, Wise R, Gillett A, Livingston R . Pharmacokinetics of Ro 13-9904, a broad-spectrum cephalosporin. Antimicrob Agents Chemother. 1980; 18(2):240-2. PMC: 283977. DOI: 10.1128/AAC.18.2.240. View

Haradahira T, Zhang M, Maeda J, Okauchi T, Kawabe K, Kida T . A strategy for increasing the brain uptake of a radioligand in animals: use of a drug that inhibits plasma protein binding. Nucl Med Biol. 2000; 27(4):357-60. DOI: 10.1016/s0969-8051(00)00096-2. View

OSullivan J, Norman A, McCready V, Flux G, Buffa F, Johnson B . A phase 2 study of high-activity 186Re-HEDP with autologous peripheral blood stem cell transplant in progressive hormone-refractory prostate cancer metastatic to bone. Eur J Nucl Med Mol Imaging. 2006; 33(9):1055-61. DOI: 10.1007/s00259-005-0010-5. View

Liepe K, Hliscs R, Kropp J, Runge R, Knapp Jr F, Franke W . Dosimetry of 188Re-hydroxyethylidene diphosphonate in human prostate cancer skeletal metastases. J Nucl Med. 2003; 44(6):953-60. View

Ogawa K, Mukai T, Inoue Y, Ono M, Saji H . Development of a novel 99mTc-chelate-conjugated bisphosphonate with high affinity for bone as a bone scintigraphic agent. J Nucl Med. 2006; 47(12):2042-7. View

10.

Ogawa K, Mukai T, Asano D, Kawashima H, Kinuya S, Shiba K . Therapeutic effects of a 186Re-complex-conjugated bisphosphonate for the palliation of metastatic bone pain in an animal model. J Nucl Med. 2007; 48(1):122-7. View

11.

Takamura N, Maruyama T, Chosa E, Kawai K, Tsutsumi Y, Uryu Y . Bucolome, a potent binding inhibitor for furosemide, alters the pharmacokinetics and diuretic effect of furosemide: potential for use of bucolome to restore diuretic response in nephrotic syndrome. Drug Metab Dispos. 2005; 33(4):596-602. DOI: 10.1124/dmd.104.002782. View

12.

Ogawa K, Mukai T, Arano Y, Ono M, Hanaoka H, Ishino S . Development of a rhenium-186-labeled MAG3-conjugated bisphosphonate for the palliation of metastatic bone pain based on the concept of bifunctional radiopharmaceuticals. Bioconjug Chem. 2005; 16(4):751-7. DOI: 10.1021/bc040249w. View

13.

Yamaoka K, Nakagawa T, Uno T . Statistical moments in pharmacokinetics. J Pharmacokinet Biopharm. 1978; 6(6):547-58. DOI: 10.1007/BF01062109. View

14.

Eshima D, Eshima L, Hansen L, Lipowska M, Marzilli L, Taylor Jr A . Effect of protein binding on renal extraction of 131I-OIH and 99mTc-labeled tubular agents. J Nucl Med. 2001; 41(12):2077-82. View

15.

Takamura N, Maruyama T, Otagiri M . Effects of uremic toxins and fatty acids on serum protein binding of furosemide: possible mechanism of the binding defect in uremia. Clin Chem. 1998; 43(12):2274-80. View

16.

de Klerk J, van Dieren E, van het Schip A, Hoekstra A, Zonnenberg B, van Dijk A . Bone marrow absorbed dose of rhenium-186-HEDP and the relationship with decreased platelet counts. J Nucl Med. 1996; 37(1):38-41. View

17.

Stabin M, Sparks R, Crowe E . OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005; 46(6):1023-7. View

18.

Takamura N, Haruta A, Kodama H, Tsuruoka M, Yamasaki K, Suenaga A . Mode of interaction of loop diuretics with human serum albumin and characterization of binding site. Pharm Res. 1996; 13(7):1015-9. DOI: 10.1023/a:1016098305796. View

19.

Uehara T, Jin Z, Ogawa K, Akizawa H, Hashimoto K, Nakayama M . Assessment of 186Re chelate-conjugated bisphosphonate for the development of new radiopharmaceuticals for bones. Nucl Med Biol. 2007; 34(1):79-87. DOI: 10.1016/j.nucmedbio.2006.10.001. View

20.

Taylor Jr A, Eshima D, Christian P, Wooten W, Hansen L, McElvany K . Technetium-99m MAG3 kit formulation: preliminary results in normal volunteers and patients with renal failure. J Nucl Med. 1988; 29(5):616-22. View