Intraocular Pharmacokinetics Using Microdialysis

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Gunnarson et al. (22) first utilized in vivo dialysis technique to sample the vitreous chamber. Studies were carried out to measure endogenous amino acids in the preretinal vitreous space. The effects of high potassium and nipecotic acid, a potent gamma-aminobutyric acid (GABA) inhibitor, on amino acid concentrations were measured. A dialysis probe was implanted in the vitreous of the eye of albino rabbits (Fig. 1). The integrity of the blood-retinal barrier was demonstrated by measuring the concentrations of 3HOH and [14C] | mannitol in the vitreous effluent following intracarotid injections. 3HOH was detected in the vitreous within a few minutes, whereas [14C]mannitol was mostly excluded. Among the amino acids, glutamine had a concentration similar to that in the plasma and cerebrospinal fluid (CSF). Vitreous concentration of all amino acids was lower than in plasma, the majority being below 50% of the plasma concentrations. The taurine level was approximately 70% that of plasma. A comparison with CSF shows that all amino acids except for glutamine and phosphoethanolamine (PEA) are present at higher concentrations in vitreous. Taurine was significantly elevated (fourfold) in the vitreous, as are valine and alanine. Perfusion with 125

Figure 1 (Top) The positioner device for the dialysis probe on the rabbit eye. The Perspex cylinder (a) is sewn to the sclera. The probe (b) is placed in the guide channel (c). The prismatic lens (d) used for biomicroscopy is in contact with the cornea. (Bottom) The biomicroscopic view of the fundus and the inserted dialysis loop (e). The iris (f) and the retina (g) can also be observed through the lens.

Figure 1 (Top) The positioner device for the dialysis probe on the rabbit eye. The Perspex cylinder (a) is sewn to the sclera. The probe (b) is placed in the guide channel (c). The prismatic lens (d) used for biomicroscopy is in contact with the cornea. (Bottom) The biomicroscopic view of the fundus and the inserted dialysis loop (e). The iris (f) and the retina (g) can also be observed through the lens.

mM KCl-containing media for 30 minutes, 4 hours after probe implantation raised the taurine content by sixfold and PEA content by twofold. Other amino acids remained unchanged (Fig. 2). Perfusion with 60 mM nipecotic acid increased GABA concentration by 60 times and taurine levels by almost 10 times, while other amino acids remained fairly constant (Fig. 3).

Ben-Nun et al. (10) evaluated the intraocular pharmacokinetics of gentamicin after intravitreal administration. The experiments were carried out for a short duration in domestic cats weighing 2.5-5 kg. The animals were anesthetized and the pupils were dilated with tropicamide 0.5% and phenylephrine 10%. Lateral canthotomy was performed in both eyes and the area of the upper part of the sclera was exposed. The superior rectus muscle was divided and cotton wool was inserted into the gap between the posterior sclera and the superior margin of the orbit to stop bleeding. The cotton wool was fixed with a drop of cyanoacrylate glue. A rubber disk (5 mm in diameter and 1 mm thick) was glued to the sclera over the pars plana region in the superotemporal quadrant of each eye. A 1 mm diameter hole was made through the rubber disks and a 20 gauge needle was then passed through each hole into the eye. A sampling catheter for ocular dialysis was

Figure 2 Change of amino acid concentration with time. (O) Amino acid level on perfusion with Krebs-Ringer buffer. (*) Level on perfusion with high potassium.
Breaching Endothelial Cells
Figure 3 Change of concentration of taurine, phosphoethanolamine, and GABA in response to 60 mM nipecotic acid. The change from Krebs-Ringer buffer to nipecotic acid perfusion media is indicated by an arrow on the time axis.

passed into the sclerotomy site in each eye and glued by a drop of cyanoa-crylate glue, followed by a drop of rapid setting epoxy adhesive. The catheters were connected in parallel to a double barrel Harvard pump and perfused at a rate of 3.5 mL/min (Fig. 4). Gentamicin was administered at a site away from the sampling site. The experiments were carried in two groups of cats: normal and bacterial endophthalmitis (Staphylococcus

Figure 4 Diagram representing the bilateral simultaneous sampling of vitreous humor by ocular dialysis.

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