title: Penetration of bevacizumab and ranibizumab through retinal pigment epithelial layer in vitro.
abstract: OBJECTIVE
  To determine the permeability of bevacizumab and ranibizumab through highly-polarized retinal pigment epithelial (RPE) cells in vitro.
  
  
  METHODS
  Highly-polarized RPE cells were cultured in the upper chamber of a Transwell culture system. Bevacizumab or ranibizumab was added to the upper chamber. After 3 hours, the concentrations of bevacizumab or ranibizumab were determined in the upper and lower chambers. The cytotoxicities of the two anti-vascular endothelial growth factor agents were determined histologically. The effects of inhibiting endocytosis by pharmacologic inhibitors were also evaluated.
  
  
  RESULTS
  The concentration of ranibizumab was higher than that of bevacizumab in the lower chamber (P < 0.05). Vascular endothelial growth factor was found mainly in the lower chamber under normal conditions. However, the concentration of vascular endothelial growth factor in the lower chamber was significantly less when ranibizumab was added to the upper chamber than when bevacizumab was added. Histology showed no obvious changes in bevacizumab-exposed or ranibizumab-exposed RPE cells. Pretreatment with protein kinase C inhibitor staurosporine had significant negative effects on the permeability of bevacizumab and ranibizumab (P < 0.05).
  
  
  CONCLUSIONS
  Ranibizumab is more permeable than bevacizumab through the highly-polarized RPE layer at clinically equivalent concentrations, and their permeability was partially protein kinase C-dependent. Ranibizumab might be more therapeutically effective than bevacizumab on choroidal neovascularization beneath the RPE layer.
authors: *Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; and †Department of Ophthalmology, Kyushu University, Fukuoka, Japan.
authors: Hiroto
authors: H
authors: Terasaki
authors: Taiji
authors: T
authors: Sakamoto
authors: Makoto
authors: M
authors: Shirasawa
authors: Naoya
authors: N
authors: Yoshihara
authors: Hiroki
authors: H
authors: Otsuka
authors: Shozo
authors: S
authors: Sonoda
authors: Toshio
authors: T
authors: Hisatomi
authors: Tatsuro
authors: T
authors: Ishibashi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000633:toxicity; D000068258:Bevacizumab; D002478:Cells, Cultured; D017097:Electric Impedance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D020287:In Situ Nick-End Labeling; D046529:Microscopy, Electron, Transmission; D010539:Permeability; D000069579:Ranibizumab; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D004791:Enzyme Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D000068258:Bevacizumab; D019311:Staurosporine; D000069579:Ranibizumab