title: Serum protein binding displacement: theoretical analysis using a hypothetical radiopharmaceutical and experimental analysis with 123I-N-isopropyl-p-iodoamphetamine.
abstract: BACKGROUND
  The binding of radiopharmaceutical to serum proteins is thought to be an important factor that restricts its excretion and accumulation in tissue. We calculated the effect of inhibitors of serum protein binding using a hypothetical radiopharmaceutical. In vitro experiments and protein binding inhibitor-loaded monkey scintigraphy were then conducted using (123)I-N-isopropyl-p-iodoamphetamine (IMP) as the radiopharmaceutical.
  
  
  METHODS
  Free fraction ratios of radiopharmaceutical were calculated with one radiopharmaceutical, two serum proteins and two specific inhibitors in the steady state at various serum protein concentrations. In vitro protein binding inhibition studies using human, rat and monkey sera were performed with site-selective displacers of specific binding sites: 400 microM 6-methoxy-2-naphthylacetic acid (6MNA; a major nabumeton metabolite) as a serum albumin Site II inhibitor and 400 microM erythromycin (ETC) as an alpha(1)-acid glycoprotein (AGP) site inhibitor. Scintigraphy with or without 6MNA loading of monkeys was performed.
  
  
  RESULTS
  The theoretical findings roughly corresponded to the experimental results. Approximately 75% of IMP bound to serum albumin Site II and AGP in the species examined. The free fraction of IMP (25.0+/-0.6% for human, 22.8+/-0.4% for monkey, 23.7+/-0.3% for rat) increased with loading of specific protein binding inhibitors (6MNA: 28.0+/-0.3% for human, 24.5+/-0.7% for monkey, 24.3+/-0.2% for rat; ETC: 26.3+/-0.4% for human, 29.5+/-1.1% for monkey, 26.0+/-0.7% for rat) and was serum protein concentration dependant based on the results of calculations. Simultaneous administration of 6MNA and ETC produced a higher free fraction ratio of IMP (31.9+/-1.0% for human, 34.6+/-0.4% for monkey, 27.0+/-0.3% for rat) than summation of the single administrations of 6MNA and ETC (domino effect) in human, rat and monkey sera. Rapid cerebral accumulation was observed with 6MNA loading in monkey scintigraphy.
  
  
  CONCLUSIONS
  6MNA appears to change the pharmacokinetics and brain accumulation of IMP in monkeys. Further studies in human are required.
authors.affiliation: Division of Health Science, Graduate School of Health Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 9200-942, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawai
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishii
authors.forename: Naoto
authors.initials: N
authors.lastname: Shikano
authors.forename: Nobuo
authors.initials: N
authors.lastname: Makino
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kuga
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Seishi
authors.initials: S
authors.lastname: Jinnouchi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nagamachi
authors.forename: Shozo
authors.initials: S
authors.lastname: Tamura
authors.forename: Norito
authors.initials: N
authors.lastname: Takamura
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001798:Blood Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D004347:Drug Interactions; D004917:Erythromycin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D000882:Haplorhini / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D020367:Iofetamine / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008024:Ligands; D008954:Models, Biological; D009280:Naphthaleneacetic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D009961:Orosomucoid / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D019275:Radiopharmaceuticals / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D012709:Serum Albumin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D051598:Whole Body Imaging
chemical_list: D001798:Blood Proteins; D008024:Ligands; D009280:Naphthaleneacetic Acids; D009961:Orosomucoid; D019275:Radiopharmaceuticals; D012709:Serum Albumin; D004917:Erythromycin; C044612:6-methoxy-2-naphthylacetic acid; D020367:Iofetamine