and that for fluorescein monoglucuronide 0.07 ± 0.01/h. After addition of probenecid, the rate of fluorescein loss was reduced to 0.13/h with less effect on the rate of clearance of metabolite, fluorescein monoglucuronide. Since fluorescein is eliminated via the posterior route, a probenecid-sensitive transport process was suggested to be involved in fluorescein transport from vitreous to retina (Kitano and Nagataki 1986) which could be related to Oat and Oct transporters discussed previously.

The involvement of an oligopeptide transporter system on the distribution of a model labelled peptide [3H] glycylsarcosine has been demonstrated. At steady state, the area under the curve (AUC) detailing the penetration rate of the peptide from vitreous to plasma was shown to be 1.61 ± 0.49 nmol min/mL. After the addition of peptide transporter substrates, glucylproline, carnosine and captopril, the uptake of the model peptide was inhibited. In addition, when non-peptide transporter substrates were added, no effect on uptake rate was noted (Atluri et al. 2003).

P2Y2 is a G protein coupled receptor known to have involvement in transfer of extracellular nucleotides. The impact of this transporter system on drug clearance was investigated using P2Y2 receptor agonists, UTP and INS542, administered by intravitreal injection to rabbits, together with fluorescein. UTP had no effect on fluorescein levels; leading the author to conclude that it was likely that UTP was degraded in the vitreous before exerting an effect on the receptor. INS542, on the other hand, significantly reduced fluorescein to metabolite fluorescein glucuronide ratios in the vitreous, when compared to eyes dosed with phosphate-buffered saline instead of agonist. Therefore, a larger proportion of the administered fluorescein was transferred out of the vitreous into the retina after administration of the agonist. This increase in transport is likely due to P2Y2 receptor activation (Takahashi et al. 2004).

A retinal transporter has also been suggested to be important for the elimination of anti-VEGF agent bevacizumab although the specific mechanisms involved has not been elucidated (Heiduschka et al. 2007).

From the studies described, it is apparent that drug transporters will play a key role in intravitreal drug delivery. Understanding the extent of the effect of specific transporter subgroups on specific ocular treatments could markedly improve drug targeting to the retina, improving therapeutic options and disease prognosis.

6.7  The Ageing Vitreous

6.7.1  Underlying Mechanisms of Vitreous Degeneration

With age, the vitreous humour undergoes progressive structural and biochemical changes (Sebag 1998; Bishop 2000; Ciferri and Magnasco 2007). Neither the vitreous humour nor the inner limiting membrane undergo renewal in later life and do not regenerate after vitrectomy. Halfter et al. describe the detachment of the vitreous body from the inner limiting membrane as consequences of the low synthetic rate and deterioration (Halfter et al. 2005). These processes are usually associated with vitreous syneresis (contraction) and synchisis (liquefaction), the rate of occurrence increasing with age.