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G. DiSandro, S. S. Samudre, P. B. Williams, M. Billy, M. Frazier, E. R. Crouch, Jr., F. A. Lattanzio, Jr.; Ocular Pharmacokinetics of Lipophilic and Hydrophilic Synthetic Cannabinoids in an Artificially Perfused Rat Eye Model. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1209.
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© ARVO (1962-2015); The Authors (2016-present)
Topical administration of potent synthetic cannabinoids alleviates glaucomatous symptoms of elevated intraocular pressure (IOP) and associated retinopathy. Although water soluble compounds are more easily solubilized and formulated, their ocular penetration is a concern. In this experiment, pharmacokinetics of water soluble O-2545 were compared with lipid soluble O-1812, using microdialysis sampling of an artificially perfused rat eye.
Sprague Dawley rats were euthanized and artificially perfused with buffered saline (5 ml/min) to maintain mean systemic blood pressure of 80 mmHg. Microdialysis probes were surgically implanted in the aqueous and vitreous chambers of the eye and dialyzed with buffered saline (1 µl/min). Synthetic cannabinoids, O-1812 or O-2545, were applied topically. Dialysate was collected every 10 min. Cannabinoid content was quantitated using high performance liquid chromatography (HPLC). The efficacy of each drug was determined as the effect on intraocular pressure (IOP). IOP was measured using a Goldman applanation tonometer.
After a single topical application (20 µl) of O-1812 (24 mM), concentration in the anterior chamber after 30 min was 7.8 nM and 1.3 nM after 120 min. In the posterior chamber the concentration of O-1812 was 4.8 nM after 30 min and 1.1 nM after 120 min. In parallel, IOP was reduced by 26 ± 1.4 % after 30 min and by 38 ± 0.7 % after 120 min. Under similar conditions, concentration of O-2545 (24 mM) after 30 min in the anterior chamber was 3.2 nM and 3.0 nM in the posterior chamber. At 120 min there was no trace of O-2545 in either chamber. After 30 min, IOP was reduced by 18 ± 6.6% and by 13 ± 3.5% after 120 min. O-1812 significantly decreased IOP compared to O-2545 (p<0.03).
Preliminary results indicated ocular penetration of lipophilic O-1812 was greater than hydrophilic O-2545. The magnitude of their effect on IOP was proportional to the concentration in the anterior chamber. The amount in the posterior chamber is important since both compounds not only decrease IOP but also have neuroprotective effects on retinal function.
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