The intraocular delivery and maintenance of therapeutic levels of pharmacological agents continues to be a vexing problem. A major impediment to the development and assessment of improved drugs, delivery systems and new approaches to therapy has been the inability to precisely measure the intraocular pharmacokinetics of medications. A recently developed, highly sensitive system permits rigorous in-vivo pharmacokinetic analysis in the aqueous and vitreous humors. This novel approach avoids the problems of pharmacokinetic methods based upon data pooled from different subjects. This system will be used to further characterize basic pharmacokinetic mechanisms in the aqueous and vitreous humors. These findings will be used to develope a forecasting model that eventually will be applied to human clinical situations.
The specific aims of this proposal are to further characterize the system in rabbit eyes and to determine the physiologic factors which regulate drug entry and elimination from the eye following direct or IV administration. Several relevant pharmacological questions including the effect of the mode of drug administration, hydrophobicity and protein binding on penetration will be addressed. The effect of infection and surgical manipulation on ocular pharmacokinetics will be characterized. Antibiotics assays will employ a microbiological assay or HPLC. Protein binding will be measured using ultracentrifugation; and hydrophobicity by octonol/water partitioning determined spectrophotometrically. A computer program will be used to perform pharmacokinetic analysis by non-linear least squares regression of complete concentration-time serum and ocular drug curves. Data will be fit to standard mathematical models. The generated data will provide an essential preliminary step in developing a cognitive approach to the choice of : a] antibiotic; b] route of administration; c] initial dosage; d] frequency of subsequent doses; e] surgical intervention (eg: vitrectomy) as it effects ocular pharmacokinetics. While we have focused on the therapy of bacterial endophthalmitis, the studies are applicable to the investigation of other classes of ocular pharmaceuticals.
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