Abstract
Direct intravitreal injection of drug is a common method for treating diseases of the retina or vitreous. The stagnant nature of the vitreous humor and surrounding tissue barriers creates concentration gradients within the vitreous that must be accounted for when developing drug therapy. The objective of this research was to study drug distribution in the vitreous humor of the rabbit eye after an intravitreal injection, using a finite element model. Fluorescein and fluorescein glucuronide were selected as model compounds due to available experimental data. All required model parameters were known except for the permeability of these compounds through the retina, which was determined by fitting model predictions to experimental data. The location of the intravitreal injection in the experimental studies was not precisely known; therefore, several injection locations were considered, and best-fit retinal permeability was determined for each case. Retinal permeability of fluorescein and fluorescein glucuronide estimated by the model ranged from 1.94×10−5 to 3.5×10−5 cm s−1 and from 0 to 7.62×10−7 cm s−1, respectively, depending on the assumed site of the injection. These permeability values were compared with values previously calculated from other models, and the limitations of the models are discussed. Intravitreal injection position was found to be an important variable that must be controlled in both experimental and clinical settings.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- C:
-
concentration of drug (g ml−1)
- D:
-
diffusivity (cm2 s−1)
- P:
-
pressure (g cm−1 s−2 or μPa)
- t:
-
time (sec)
- \(\vec U\) :
-
velocity vector (cm s−1)
- μ:
-
viscosity (g s−1 cm−1)
- ρ:
-
density (g cm−3)
- ∇:
-
grad (vector operator)
- ·:
-
dot product (vector operator)
- n:
-
normal direction
- t1,t2:
-
tangential directions
References
Araie, M., and D. M. Maurice. The loss of fluorescein, fluorescein glucuronide and fluorescein isothiocyanate dextran from the vitreous by the anterior and retinal pathways.Exp. Eye Res. 52:27–39, 1991.
Davis, B. K. Diffusion in polymer gel implants.Proc. Natl. Acad. Sci U.S.A. 71:3120–3123.
Forster, R. K., R. L. Abbott, and H. Gelender. Management of infectious endophthalmitis.Ophthalmology 87:313–319, 1980.
Hosaka, A. Permeability of the blood-retinal barrier in myopia. An analysis employing vitreous fluorophotometry and computer simulation.Acta Ophthalmol. Suppl. 185:95–99, 1988.
Kinsey, V. E., and D. V. N. Reddy. Chemistry and dynamics of aqueous humor. In: The rabbit eye in research, edited by J. H. Prince. Springfield: C. C Thomas, 1964, pp. 218–319.
Koyano, S., M. Araie, and S. Eguchi. Movement of fluorescein and its glucuronide across retinal pigment epithelium-choroid.Invest. Ophthalmol. Vis. Sci. 34: 531–538, 1993.
Larsen, J., H. Lund-Andersen, and B. Krogsaa. Transient transport across the blood-retina barrier.Bull. Math. Biol. 45:749–758, 1983.
Lee, V. H. L., K. J. Pince, D. A. Frambach,et al. Drug delivery to the posterior segment. In: Retina, edited by T. E. Ogden and A. P. Schachat. St. Louis: C. V. Mosby, 1989, pp. 483–498.
Lund-Andersen, H., B. Krogsaa, M. la Cour, and J. Larsen. Quantitative vitreous fluorophotometry applying a mathematical model of the eye.Invest. Ophthalmol. Vis. Sci. 26:698–710, 1985.
Lund-Andersen, H., B. Krogsaa, and J. Larsen. Calculation of the permeability of the blood-retinal barrier to fluorescein.Graef. Arch. Clin. Exp. Ophthalmol. 222: 173–176, 1985.
McDonnell, J. H. Ocular embryology and anatomy. In: Retina: basic science, inherited retinal disease, and tumors, vol. 1, edited by T. E. Ogden, St. Louis: C. V. Mosby Company, 1989, pp. 1–12.
Ogura, Y., Y. Tsukahara, I. Saito, and T. Kondo. Estimation of the permeability of the blood-retinal barrier in normal individuals.Invest. Ophthalmol. Vis. Sci. 26:969–976, 1985.
Ohtori, A., and K. Tojo. In vivo/in vitro correlation of intravitreal delivery of drugs with the help of computer simulation.Biol. Pharm. Bull. 17:283–290, 1994.
Palestine, A. G., and R. F. Brubaker. Pharmacokinetics of fluorescein in the vitreous.Invest. Ophthalmol. Vis. Sci. 21:542–549, 1981.
Pflugfelder, S. C., E. Hernandez, S. J. Fliesler, J. Alvarez, M. E. Pflugfelder, and R. K. Forster: intravitreal vancomycin. Retinal toxicity, clearance, and interaction with gentamicin.Arch. Ophthalmol. 105:831–837. 1987.
Stainer, G. A., G. A. Peyman, H. Meisels, and G. Fishman. Toxicity of selected antibiotics in vitreous replacement fluid.Ann. Ophthalmol. 9:615–618, 1977.
Tabatabay, C. A., D. J. D'Amico, L. A. Hanninen, and K. R. Kenyon, Experimental drusen formation induced by intravitreal aminoglycoside injection.Arch. Ophthalmol. 105:826–830, 1987.
Talamo, J. H., D. J. D'Amico, L. A. Hanninen, K. R. Kenyon, and E. T. Shanks. The influence of aphakia and vitrectomy on experimental retinal toxicity of aminoglycoside antiobiotics.Am. J. Ophthalmol. 100: 840–847, 1985.
Tojo, K., and A. Ohtori. Pharmacokinetic model of intravitreal drug injection.Math. Biosci. 12359–12375, 1994.
Yoshida, A., S. Ishiko, and M. Kojima. Outward permeability of the blood-barrier barrier.Graef. Arch. Clin. Exp. Ophthalmol. 230:78–83, 1992.
Yoshida, A., M. Kojima, S. Ishiko,et al. Inward and outward permeability of the blood-retinal barrier. In: Ocular fluorophotometry and the future, edited by J. Cunha-Vaz and E. Leite. Amsterdam: Kugler & Ghedini Publishers, 1989, pp. 89–97.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Friedrich, S., Cheng, YL. & Saville, B. Finite element modeling of drug distribution in the vitreous humor of the rabbit eye. Ann Biomed Eng 25, 303–314 (1997). https://doi.org/10.1007/BF02648045
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02648045