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Effect of retinal permeability, diffusivity, and aqueous humor hydrodynamics on pharmacokinetics of drugs in the eye.

Authors
  • Krishnamoorthy, Mahesh K1
  • Park, Juyoung
  • Augsburger, James J
  • Banerjee, Rupak K
  • 1 Department of Mechanical Engineering, University of Cincinnati, Cincinnati, OH 45221-0072, USA.
Type
Published Article
Journal
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics
Publication Date
Jun 01, 2008
Volume
24
Issue
3
Pages
255–267
Identifiers
DOI: 10.1089/jop.2007.0111
PMID: 18476798
Source
Medline
Language
English
License
Unknown

Abstract

Retinal permeability is one of the important parameters that determine drug distribution during diseased retinal conditions, whose effect is still unclear. Thus, the main aim of this study was to understand the influence of varying retinal permeability (P) on drug distribution under normal (F1) and elevated vitreous outflow pathophysiologic conditions (F10) for a wide variety of drug diffusivities-high: D(-5) and low: D(-7). A computational model of the rabbit eye was developed that took into account the varying effects of convection during normal and pathophysiologic conditions. High retinal permeability, P(-5), is associated with low peak macular concentration and a rapid clearance from the ocular chambers, with the retina as the major route of elimination. For low permeability, P(-7), there is very high peak macular concentration, slow elimination, and a buildup of drug concentration, which depends on vitreous outflow. The variation of t(1/2) with P was found to be of linear and nonlinear trends for F1 and F10 flow cases, respectively. Moreover, for D(-5) diffusivity, there was a 1.5-fold increase and a 1.6-fold decrease in t(1/2) values when the retinal permeability values were P(-5) and P(-7). On the contrary, for D(-7) diffusivity, there was a 2.5-fold decrease and a 1.4-fold increase in t(1/2) values for P(-5) and P(-7), with t(1/2) increasing for P(-6) during both high and low diffusivities. Thus, the combined effect of variables P, D, and F are important factors that should be considered in order to determine drug dosage. This study could be used to estimate the drug distribution and elimination for (1) wide range of physicochemical properties of drugs and (2) normal and abnormally elevated vitreous flows during the diseased condition of the eye. These results could help in obtaining essential information about the treatment protocol for targeted retinal diseases while simultaneously avoiding the toxic effects of these drugs.

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