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A.R. Spitze, F.A. Lattanzio, Jr, R.C. Allen, I. Castillo, P.B. Williams; Human Corneal Penetration by Topical Formulations of the Synthetic Endocannabinoid, WIN 55–212–2 . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3783.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: WIN 55212–2 (WIN), a synthetic endocannabinoid, has significantly different chemical properties from THC, the active compound in marijuana. Both possess beneficial IOP–lowering and neuroprotective effects potentially suitable for glaucoma therapy, but conversely, both also have undesirable systemic effects. Topical WIN administration has the potential to minimize systemic effects, but evidence that selected WIN formulations cross the human cornea without damage is lacking. Methods: To determine corneal penetration and transcorneal flux, human corneas were mounted in an Ussing chamber with the epithelium facing the "extraocular" side of the chamber. Admixtures of tritiated (3H) and non–tritiated WIN (0.125 – 1.0%) were dissolved in TocrisolveTM (Tocris, Ellisville, MO) and added to the "extraocular" side of chamber, while samples were collected from the "intraocular" chamber at selected intervals over 24hr. 3H WIN in the samples and the cornea was measured by liquid scintillation counting. Other intraocular samples were examined by mass spectrometry (MS) using a Bruker Ultraflex TOF–TOF and a Ciphergen SELDI to determine if MS would be suitable to detect non–radioactively labeled endocannabinoids. Results and Conclusions: WIN successfully penetrated and crossed the human cornea with a rate constant of 0.008%/hr. While concentration and time–dependent, transport was saturable at >0.5% WIN. When 50 microliters of 1% WIN was added to the corneal surface, WIN corneal concentration within 15 min was 27.9% of its 24 hr steady state. At 24 hr, the intraocular WIN concentration was 1.66+0.53 micromolar while the corneal WIN concentration was 20.05+5.59 micromolar, implicating the cornea as a slow–release intraocular drug depot. Neither WIN nor TocrisolveTM had adverse effects on corneal integrity as measured by confocal microscopy. WIN concentrations similar to those occurring during transport (nano to micromolar range) could be readily measured by MS, suggesting that MS may be useful for both in vitro and in vivo cannabinoid pharmacokinetic measurements.
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