title: Structural changes in albumin are a possible mechanism for fluctuation of cefazorin and ibuprofen plasma protein binding in rats with carcinogen-induced osteosarcoma.
abstract: OBJECTIVE
  It is known that the protein-unbound fraction (fp) of warfarin fluctuates in the plasma of cancer patients and the fluctuation of fp is correlated with albumin concentration. However, this mechanism remains unclear. The present study was performed with the objective of elucidating variations in the protein-binding rate of specific drugs in the presence of cancer, as well as the mechanisms involved.
  
  
  METHODS
  Experiments were performed using Fisher 344 model rats, that we have used in previous studies. A single i.v. injection of cefazolin (CEZ) 20 mg/kg or ibuprofen (IB) 10 mg/kg was administered to both tumor-bearing and control groups. We compared relevant pharmacokinetics. Purified albumin was checked for purity with SDS-PAGE and was used in experiments on protein binding of CEZ and IB.
  
  
  RESULTS
  The fp of CEZ in plasma from the tumor-bearing group increased approximately 2.9-fold and the fp of IB also increased about 2.7-fold. For that reason, we purified albumin from plasma and examined its spectroscopic signature. We showed that conformational changes (i.e., decreases in the hydrophobic region, increases in endogenous tryptophan fluorescence intensity and decrease in α-helical content) had occurred in albumin in the tumor-bearing group.
  
  
  CONCLUSIONS
  In the present study, we confirmed that, in a state of cancer morbidity, fp was elevated for site I high-affinity CEZ and site II high-affinity IB. Moreover, our findings indicated that, as a cause of those elevations, a decrease in the albumin concentration and conformational changes due to an oxidation are involved.
authors: Department of Pharmacy, Hekinan Municipal Hospital, Aichi, Japan Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan.
authors: Yukari
authors: Y
authors: Itakura
authors: Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan.
authors: Shino
authors: S
authors: Taga
authors: Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan.
authors: Chieko
authors: C
authors: Iwata
authors: Laboratory of Clinical Pharmacy, Gifu Pharmaceutical University, Gifu, Japan.
authors: Hitomi
authors: H
authors: Teramachi
authors: Department of Pharmacy, Kanazawa University Hospital, Kanazawa, Japan.
authors: Ken-Ichi
authors: K
authors: Miyamoto
authors: Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Hiroyuki
authors: H
authors: Tsuchiya
authors: Department of Laboratory Medicine, School of Medicine, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors: Takashi
authors: T
authors: Wada
authors: Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan matusita@p.kanazawa-u.ac.jp.
authors: Ryo
authors: R
authors: Matsushita
mesh_terms: D000418:Albumins / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002437:Cefazolin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage*; D012516:Osteosarcoma / Q000139:chemically induced / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats
chemical_list: D000418:Albumins; D001798:Blood Proteins; D002273:Carcinogens; D002437:Cefazolin; D007052:Ibuprofen
keywords: Plasma protein binding; albumin; cancer; osteosarcoma; oxidation; rat