Abstract
Purpose:
To study the possibility that the drainage of drug loaded ocular blood to the cavernous sinus is coupled with returned drug transfer in the opposite direction, not through the systemic circulation.
Methods:
Texas-Red labeled dextran (40-kDa) solution (2.5 mg/ml) was injected into the sub-conjunctiva of the rat eye. Eyes were enucleated and intracranial optic nerves, up to the chiasm, were harvested. Tissues were snap-frozen and processed for visualization by fluorescence microscopy. In an extension of previous brimonidine ocular pharmacokinetic study, whole-tissue brimonidine in contralateral eye tissues was quantified at 5 minutes after single topical instillation of 50µl of 3H-radiolabeled brimonidine solution (0.2%) to the right eye of albino rabbits.
Results:
In the area of the optic nerve head, dextran was heavily loaded in episcleral and periocular veins but absent in the posterior ciliary artery. In the sampled intracranial segment of the optic nerve, just before the junction with the optic-chiasm, nerve axons were free of dextran while pial and sheath veins were draining dextran towards the cavernous sinus. Whole-tissue brimonidine calculation was based on the evidenced drug concentration per gram tissue and whole-tissue weight. The sum of brimonidine accumulation at 5 min. post dosing for all tissues of the contralateral eye was 151.08±39.21 ng. The estimated amount of brimonidine that could have entered the eye via blood circulation in first 5 minutes post dosing (67.3±26.8 ng) was calculated by using previously reported value of blood flow per minute into the rabbit eye and the evidenced brimonidine concentration in the systemic blood in current study.
Conclusions:
The dextran study has shown the accumulation of dextran in the cavernous sinus area of the rat by non-systemically mediated vascular drainage. The evidenced brimonidine accumulation in the contralateral rabbit eye (151.08±39.21 ng) was significantly higher than highest possible amount of brimonidine (67.3±26.8 ng) that could be extracted from the systemic blood by contralateral eye tissues, suggesting that contralateral eye brimonidine accumulation represents in part returned drug transfer from the cavernous sinus toward the eye via non-systemic vascular connections. Further studies are needed to support the integration of the cavernous sinus in ocular pharmacokinetic modeling.
Keywords: 503 drug toxicity/drug effects