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S. S. Lee, I. Harutyunyan, D. Z. D'Argenio, R. A. Moats; The Effects of in vivo Experimental Vitreous Syneresis on Drug Diffusivity. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2453.
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Intravitreal drug delivery is increasingly becoming one of the primary modes of therapy for retinal diseases such as age-related macular degeneration and diabetic retinopathy. The majority of these patients have experienced vitreous syneresis and liquefaction due to age and disease. It is therefore, unclear how well pre-clinical pharmacokinetics performed in animals with well-formed and more viscous vitreous humors predict pharmacokinetics in more liquified human eyes. To improve our understanding of drug distribution in syneretic eyes, in vivo magnetic resonance imaging (MRI) studies were performed on rabbits to evaluate drug distribution in experimentally induced syneretic eyes.
A proteolytic enzyme cocktail consisting of collagenase, hyaluronidase, and plasmin (EMD Biosciences, Inc., San Diego, CA) was prepared to induce >90% liquefaction in the rabbit vitreous. Young Dutch belted rabbits received one injection of the proteolytic enzyme cocktail in the right eye and was subjected to a rest period of no less than two days. Both eyes of each rabbit received either 5 µL of 0.05M gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) (Magnevist, Berlex , Inc.) diluted in a crosslinked hyaluronic acid or 25 mg/mL Gd-Albumin (Biopal, Inc., Worcester, MA). Serial 3-D MRI scans were performed for up to 8 hours for each eye. Concentration was estimated from a previously determined calibration curve that related signal intensity to Gd-DTPA concentration. Diffusivity in the vitreous was estimated along one axis.
>90% liquefaction was achieved in all eyes that were administered the proteolytic cocktail and the animals tolerated the enzymes well. Drug distribution occurred faster in eyes that had experimentally induced syneresis. The average increase in diffusivity in syneretic eyes was 3 fold faster than the normal well-formed vitreous. Additionally, diffusion gradients were evident in both control and experimental eyes.
Drug distribution in enhanced in a more liquefied vitreous humor, as the diffusivity of the same agent is increased in the syneretic eye. The distribution in both types of vitreous occurs down a concentration gradient at different rates, suggesting that the vitreous composition may need to be taken into account when relating animal pharmacokinetics to human.
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