Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR)

Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5198-204. doi: 10.1167/iovs.09-5144. Epub 2010 May 5.


Purpose: To determine the pharmacokinetics of SAR 1118, a small-molecule antagonist of leukocyte function-associated antigen (LFA)-1, after administration of ophthalmic drops in normal rats, and to determine its pharmacologic activity by assessing the inhibition of retinal leukostasis and vascular leakiness in a streptozotocin (STZ)-induced diabetic retinopathy model.

Methods: The ocular pharmacokinetics of SAR 1118 were studied in rats after a single topical dose of (14)C-SAR 1118 (1 mg/eye; 40 μCi; 15.5 μL). SAR 1118 concentration time profiles in plasma and ocular tissues were quantified by liquid scintillation counting (LSC). The pharmacologic activity of SAR 1118 eye drops administered thrice daily for 2 months at 1% (0.3 mg/eye/d) and 5% (1.5 mg/eye/d) was assessed in an STZ-induced diabetic rat model by determining retinal leukostasis and blood-retinal barrier breakdown. Diabetic rats treated with periocularly administered celecoxib microparticles served as the positive control, and vehicle-treated rats served as the negative control.

Results: A single dose of 6.5% (14)C-radiolabeled SAR 1118 ophthalmic drops delivered retinal drug levels greater than 1 μM in less than 30 minutes and sustained levels greater than 100 nM for 8 hours. SAR 1118 eye drops significantly reduced leukostasis and blood-retinal barrier breakdown in a dose-dependent manner.

Conclusions: SAR 1118 ophthalmic drops administered thrice daily deliver therapeutic levels of SAR 1118 in the retina and can alleviate the retinal complications associated with diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Animals
  • Blood-Retinal Barrier / drug effects
  • Capillary Permeability / drug effects
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Retinopathy / drug therapy*
  • Diabetic Retinopathy / metabolism
  • Diabetic Retinopathy / pathology
  • Dose-Response Relationship, Drug
  • Leukostasis / prevention & control
  • Lymphocyte Function-Associated Antigen-1 / drug effects*
  • Male
  • Microscopy, Confocal
  • Ophthalmic Solutions / administration & dosage*
  • Ophthalmic Solutions / pharmacokinetics
  • Rats
  • Rats, Inbred BN
  • Rats, Sprague-Dawley
  • Retina / drug effects*
  • Retina / metabolism
  • Treatment Outcome


  • Lymphocyte Function-Associated Antigen-1
  • Ophthalmic Solutions