a Phosphorothioate oligonucleotide.

b Half-lives for ganciclovir normalized for volume and retinal surface area.

a Phosphorothioate oligonucleotide.

b Half-lives for ganciclovir normalized for volume and retinal surface area.

sivity and retinal permeability are important factors that determine elimination from the vitreous particularly in the case of blood-retinal barrier compromise (75). Furthermore, drug is eliminated faster in aphakic eyes, especially for drugs with low retinal permeability and injected proximal to the lens capsule. Injection close to the primary elimination barrier appears to be a key factor. Wingard et al. showed that intravitreally injected amphotericin B progressively accumulated in the sclera-choroid-retina in control phakic eyes, a phenomenon not observed in aphakic eyes (76). Whole phakic eye half-life was 6.9-15.1 days,while aphakic half-life was only 1.8 days. In the case of infected eyes, Ben-Nun et al. showed, with intravitreal injection of gentamicin, that the elimination rate of drug was greater in infected than normal eyes, presumably due to an alternation in blood-retinal barrier (77). In another evaluation of the vitreal kinetics of ceftizoxime, ceftriazone, ceftazindime, and cefepime in rabbits, T1/2 values ranged from 5.7 to 20 hours in rabbits with uninflamed eyes and from 9.4 to 21.5 hours in rabbits with infected eyes (78). The longer T1/2 suggested a predominant anterior route of elimination, while the shorter T1/2 and low aqueous/vitreous concentration ratios suggested retinal elimination.

As mentioned, some compounds are actively transported out of the vitreous leading to a faster elimination than expected based on physico-chemical properties; for example, Mochizuki investigated the transport of indomethacin in the anterior uvea of the albino rabbit in vitro and in vivo (intravitreal injection) (79). An energy-dependent carrier-mediated transport mechanism with low affinity was observed in the anterior uvea of the rabbit that could have accounted for the drug's rapid clearance (30% per hour) from the eye. Yoshida et al. characterized the active transport mechanism of the blood-retina barrier by estimating inward and outward permeability of the blood-retinal barrier in monkey eyes using vitreous fluorophotrometry and intravitreally injected fluorescein and fluorescein glucuronide (80). Outward permeability (Pout) was 7.7 and 1.7 x 10~4 cm/min, respectively. Pout/Pin was 160 for fluroescein and 26 for fluores-cein glucuronide. Intraperitoneal injection of probenecid caused a significant decrease in Pout for fluorescein but had no effect on fluorescein glucuronide Pout. The data suggest that fluorescein is actively transported out of the retina. In another example, Barza et al. studied the ocular pharmacokinetics of carbenicillin, cefazolin, and gentamicin following intravitreal administration to rhesus monkeys (81). Vitreal half-lives ranged from 7 to 33 hours. Concomitant intraperitoneal injection of probenecid prolonged the vitreal half-life of the cephalosporins, indicating a secretory mechanism. The results are consistent with the hypothesis that, in primates (as in rabbits), ^-lactam antibiotics are eliminated by the retinal route and aminoglycosides by the anterior route.

2. Vitreal Pharmacokinetic Models

Several models have been proposed to describe the kinetics of intra-vitreally injected drugs. The simplest models assume a well-stirred vitreous body compartment in an effort to reduce the complexity of the mathematics. This may be a closer approximation in studies employing injection volumes of 100 mL or more, where the normally nonstirred vitreous can become agitated; however, injection volumes of greater than 20 mL generally require removal of an equal volume of vitreous to avoid a precipitous rise in intraocular pressure. This act alone may alter the physiology of the vitreous body. More sophisticated modeling takes into account diffusion through the relatively stagnant vitreous humor by employing Fick's law of diffusion. For example, Ohtori and Tojo determined the elimination of dexamethasone sodium m-sulfobenzoate (DMSB) following injection in the rabbit vitreous body under in vivo and in vitro conditions (82). The rate of elimination was greater in vivo versus in vitro. A general mathematical model, based on Fick's second law of diffusion, was developed to describe the pharmacokinetics. The model assumed a cylindrical vitreous body with three major elimination pathways: posterior aqueous chamber, retina-choroid-scleral membrane, and lens (see Fig. 9). Concentration in the vitreous decreased rapidly near the posterior aqueous chamber, indicating that the annular gap between the lens and ciliary body to posterior chamber to posterior chamber to posterior chamber to posterior chamber

Figure 9 Cylindrical model of the vitreous body of rabbits. The posterior chamber, the retina-choroid-sclera (RCS), and the lens constitute elimination pathways out of the vitreous. (From Ref. 82.)

(posterior chamber) was the major route of elimination. The concentration gradient near the retina was considerable. It was concluded that, because of its large surface area, the retina can be a significant route of elimination. In a seprate study, Tojo and Ohtori used the cylindrical model approach to demonstrate three potential pathways of elimination including the annular gap, the lens, and the retina-choroid-sclera (83). The concentration in the retina was affected by the site of injection or initial distribution profiles, while concentration at the lens was independent of dose site. Drug injected into the anterior segment of the vitreous rapidly exited through the annular gap into the posterior chamber. The authors reasoned that drugs should be injected into the posterior vitreous to prolong therapeutic levels in the retina. Their results also showed that half-life was proportional to molecular weight and elimination into the lens was negli-ble due to the barrier function of the lens capsule.

Probably the most precise modeling of vitreal pharmacokinetics uses finite element analysis, a method commonly employed in engineering. This approach accounts for the detailed geometry and boundary conditions of the vitreous and precisely predicts the concentration gradients within the vitreous. Friedrich and colleagues adapted finite element modeling to the study of the drug distribution in the stagnent vitreous humor of the rabbit eye after an intravitreal injection of fluorescein and fluorescein-glucuronide (74,75,84). The computer-generated concentration profile in the vitreous humor is shown in Figure 10. Retinal permeability of fluorescein and fluorescein glucuronide were estimated by the model at 1.94 x 10~5 to 3.5 x 10~5 cm/s and from 0 to 7.62 x 10~7 cm/s, respectively. Simulations have also been performed for the human eye (74). In both rabbit and human eyes, the effect of injection position was found to be an important variable, as indicated in Figure 11 (84).

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