FUTURE CHALLENGES, MILESTONES, AND OPPORTUNITIES

VI. FUTURE CHALLENGES, MILESTONES, AND OPPORTUNITIES

The anterior segment microdialysis technique has provided the framework for novel approaches to the examination of the mechanisms involved in ophthalmic drug ocular pharmacokinetics and the pharmacodynamics of aqueous humor formation and modulation. Anesthetized and conscious animal models, in some cases involving the long-term placement of micro- dialysis probes into the anterior segment (i.e., anterior and posterior cham- bers), were established, which have provided a substantial advance in experimental approaches to ocular pharmacokinetic/pharmacodynamic experimentation. Reduction in the number of animals required for these

via reduction in costs and in animal-sparing research approaches. Animal experimentation with probe placement in the anterior segment, pioneered by Sato et al. (49), Fukada et al. (48), and Ohtori et al. (50), up to papers describing conscious animal experimental with microdialysis probes in the anterior chamber for 5 to > 30 days (17,53,54), demonstrate the rapid development and increased utility of the microdialysis approach in the study of ocular drug delivery and disposition. Unique applications of the microdialysis approach in the examination of drug ocular disposition such as a dual probe implantation technique involving simultaneous exam- ination of aqueous and vitreous drug disposition have been performed (51,52). The importance and broad-based applicability of the microdialysis sampling approach for the examination of ocular pharmacokinetics and dynamics of ophthalmics is of large impact. Reuse of animals is possible because of the long-term tolerability of the animals to probe implantation.

A series of substrates could be examined using the same subject to assess phenomenon such as tolerance development. Possible reduction in inter- subject responses to ophthalmic drugs is possible via this approach. This approach also provided the framework for a detailed examination of in vivo basal blood to aqueous transport of ascorbate, a labile substrate of utmost importance to intraocular health and homeostasis. Moreover, the

246 Rittenhouse pharmacodynamics of beta-adrenergic antagonist–associated modulation

of both aqueous humor formation and ascorbate ciliary accumulation was examined in detail using anterior segment microdialysis. Pharmacokinetic modeling was facilitated with this technique; by using alterations in the ascorbate aqueous humor time-course as a means of estimating aqueous humor flow, the modulatory effects of a model sub- strate, propranolol, on aqueous humor turnover, was examined.

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