title: The effect of Rho-associated kinase inhibition on the ocular penetration of timolol maleate.
abstract: OBJECTIVE
  To assess the effects of Rho-associated kinase (ROCK) inhibition on the intraocular penetration of timolol maleate.
  
  
  METHODS
  Ex vivo porcine corneal penetration of timolol maleate, sotalol hydrochloride, or brinzolamide incubated with or without Y-27632 was determined in vertical Franz diffusion cells. The effect of ROCK inhibition on the vasodilation of porcine conjunctival vasculature was assessed by scanning electron microscopy (SEM) and immunohistochemical staining with subsequent laser-scanning confocal microscopy (LSCM). Experiments were conducted in New Zealand White (NZW) rabbits to assess the effect of ROCK inhibition on the intraocular distribution of timolol maleate.
  
  
  RESULTS
  ROCK inhibition resulted in minimal alteration of ex vivo porcine corneal drug penetration of timolol, sotalol, or brinzolamide. SEM and LSCM experiments conducted with conjunctiva and sclera tissue in Franz diffusion cells suggested vasodilation in the conjunctival vasculature in the presence of Y-27632. Pretreatment of the eyes of NZW rabbits with Y-27632 resulted in aggregate fold reductions (1 hour, 0.25-fold; 4 hours, 0.45-fold) of timolol maleate drug concentrations in intraocular tissues (aqueous humor, lens, and iris) versus eyes not receiving Y-27632 pretreatment. Pretreatment with a vasoconstrictor, phenylephrine, resulted in a reversal of the effect of Y-27632 on diminished timolol maleate intraocular penetration in NZW rabbits.
  
  
  CONCLUSIONS
  ROCK inhibition reduced the intraocular penetration of administered timolol maleate presumably due to increased systemic elimination through the conjunctival vasculature. It is anticipated that care in order and timing of ROCK inhibitor administration will be warranted for those patients who may be on a multiple topical drug regimen for primary open-angle glaucoma.
authors: McWhorter School of Pharmacy, Samford University, Birmingham, AL 35229, USA. jarnold@samford.edu
authors: John J
authors: JJ
authors: Arnold
authors: Mark S
authors: MS
authors: Hansen
authors: Gregory S
authors: GS
authors: Gorman
authors: Toshihiro
authors: T
authors: Inoue
authors: Vasantha
authors: V
authors: Rao
authors: Simone
authors: S
authors: Spellen
authors: Ronald N
authors: RN
authors: Hunsinger
authors: Christopher A
authors: CA
authors: Chapleau
authors: Lucas
authors: L
authors: Pozzo-Miller
authors: W Daniel
authors: WD
authors: Stamer
authors: Pratap
authors: P
authors: Challa
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003228:Conjunctiva / Q000098:blood supply; D003315:Cornea / Q000378:metabolism*; D015194:Diffusion Chambers, Culture; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007498:Iris / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D013015:Sotalol / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000493:pharmacokinetics; D013552:Swine; D053719:Tandem Mass Spectrometry; D013843:Thiazines / Q000493:pharmacokinetics; D013999:Timolol / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000319:Adrenergic beta-Antagonists; D000577:Amides; D004791:Enzyme Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011725:Pyridines; D013449:Sulfonamides; D013843:Thiazines; C108830:Y 27632; D013999:Timolol; C111827:brinzolamide; D013015:Sotalol; D054460:rho-Associated Kinases