Retina-choroid-sclera permeability for ophthalmic drugs in the vitreous to blood direction: quantitative assessment.

PURPOSE: To determine the outward permeability of retina-choroid-sclera (RCS) layer for different ophthalmic drugs and to develop correlations between drug physicochemical properties and RCS permeability. METHODS: A finite volume model was developed to simulate pharmacokinetics in the eye following drug administration by intravitreal injection. The RCS permeability was determined for 32 compounds by best fitting the drug concentration-time profile obtained by simulation with previously reported experimental data. Multiple linear regression was then used to develop correlations between best fit RCS permeability and drugs physicochemical properties. RESULTS: The RCS drug permeabilities had values that ranged over 3 × 10(-6) m/s. Regression analysis for hydrophilic compounds showed that more than 92% of the variation in permeability values can be explained by correlative models of drug properties that include logarithm of the octanol-water partition coefficient (LogP), protein binding (PB), number of hydrogen bond acceptors (HBA), hydrogen bond donors (HBD), polar surface area (PSA) and dissociation constant (pKa) as independent variables. Regression analysis for lipophilic compounds showed that no significant correlation can be found between just physicochemical properties and RCS permeability. CONCLUSION: Using the RCS permeability obtained from this study for different drugs, one can predict pharmacokinetics of intravitreal drug delivery systems such as solid implants or colloidal systems. Furthermore, the developed correlations between RCS permeability and physicochemical properties of drugs are useful in early drug development by predicting RCS permeability and drug concentration in the vitreous without experimental data.

Assessment of aqueous humor dynamics in the mouse by a novel method of constant-flow infusion.

PURPOSE: To characterize a technique that concurrently assesses all aqueous humor hydrodynamic parameters in mouse eyes. METHODS: Mouse outflow facility (C) was determined by multiple flow-rate infusion and episcleral venous pressure (Pe) measured by manometry. The animals were then euthanatized, eliminating aqueous formation rate (Fin) and Pe. C was determined again (C(dead)) while uveoscleral outflow (Fu(dead)) and Fin were deduced. To assess whether Fu(dead) would remain the same as Fu(live), the animals were perfused with FITC-dextran and Fu determined. The effects of IOP-lowering drugs on the parameters of aqueous hydrodynamics were also evaluated. RESULTS: Under the conditions tested, Fu(live) (0.012 ± 0.003 µL/min) was not different from Fu(dead) (0.015 ± 0.003 µL/min; P = 0.472). In anesthetized mice, IOP = 11.4 ± 0.2 mm Hg (mean ± SEM, n = 8), C = 0.018 ± 0.0006 µL/min/mm Hg, Pe = 5.4 ± 0.2 mm Hg, Fin = 0.14 ± 0.0007 µL/min, and Fu = 0.029 ± 0.005 µL/min. C(dead) was not different from C (P = 0.317). Latanoprost reduced IOP by increasing C by 0.009 ± 0.0003 µL/min/mm Hg (P < 0.001), without affecting Fin or Fu. Betaxolol reduced Fin by 0.075 ± 0.021 µL/min (P = 0.009). Brimonidine increased C by 0.005 ± 0.0005 µL/min/mm Hg (P < 0.001) and Fu by 0.013 ± 0.003 µL/min (P = 0.007). CONCLUSIONS: In this study, a unique technique was developed to concurrently assess IOP, C, Pe, Fin, and Fu in the mouse eye. This experimental approach should be useful to evaluate effects of pharmacologic agents or genetic manipulations on aqueous humor dynamics in mice and other animal models.

Dynamic eye phantom for retinal oximetry measurements.

Measurements of oxygen saturation and flow in the retina can yield information about eye health and the onset of eye pathologies such as diabetic retinopathy. Recently, we developed a multiaperture camera that uses the division of the retinal image into several wavelength-sensitive subimages to compute retinal oxygen saturation. The calibration of such instruments is particularly difficult due to the layered structure of the eye and the lack of alternative measurement techniques. For this purpose, we realize an in vitro model of the human eye composed of a lens, the retina vessel, and three layers: the choroid, the retinal pigmented epithelium, and the sclera. The retinal vessel is modeled with a microtube connected to a micropump and a hemoglobin reservoir in a closed circulatory system. Hemoglobin oxygenation in the vessel could be altered using a reversible fuel cell. The sclera is represented by a Spectralon slab. The optical properties of the other layers are mimicked using titanium dioxide as a scatterer, ink as an absorber, and epoxy as a supporting structure. The optical thickness of each layer of the eye phantom is matched to each respective eye layer.

Comparative assessment of distribution of blackcurrant anthocyanins in rabbit and rat ocular tissues.

Anthocyanins (ACs) are phenolic compounds that are distributed widely in fruits and vegetables. Although consumption of these compounds has been shown to improve visual function, the distribution of ACs in ocular tissue has not been examined in detail. The aim of this study was therefore to evaluate the ocular distribution of blackcurrant anthocyanins (BCAs) in rats and rabbits after oral, intravenous (i.v.) and intraperitoneal (i.p.) administration. Identification and quantification of ACs were carried out using high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS) and high-performance liquid chromatography (HPLC) with UV-visible detection, respectively. BCAs were identified in the plasma and whole eye after oral and i.p. administration in rats. No other peaks were detected in either plasma or ocular tissues after administration when the absorbance of the eluate was monitored at 520 nm. This finding indicates that intact forms of ACs were present in rats after administration of BCA. In rats given i.p. administration, the concentration of total ACs in the whole eye and some ocular tissues was higher than that measured in plasma. These results suggested that ACs detected in the ocular tissues were not due to residual blood. Following i.v. administration in rabbits, four ACs were identified in the plasma and several ocular tissues including the aqueous humor, cornea, sclera, choroid, ciliary body, iris and retina. A small amount of ACs was also detected in the vitreous and lens. In conclusion, this study demonstrated that BCAs were absorbed and distributed in ocular tissues as intact forms. Our data show clearly that intact forms of BCAs pass thorough the blood-aqueous barrier and blood-retinal barrier in both rats and rabbits.