Evaluation of microdialysis sampling of aqueous humor for in vivo models of ocular absorption and disposition

The dynamics of β-adrenergic-associated reductions in aqueous humor production for treatment of elevated intraocular pressure are not well understood. In particular, the relationship between ocular pharmacokinetics and pharmacodynamics has yet to be established. This study was undertaken to develop a procedure for examining the ocular absorption and disposition of topically administered ophthalmic β-adrenergic antagonists in individual animals. Dogs were anesthetized with isoflurane and a microdialysis probe was implanted in the anterior chamber of one eye and perfused with 0.9% saline at a rate of 2 μl min^-1. ³H-propranolol was administered by intracameral injection or topically. Each dog received intracameral and topical propranolol, in alternate eyes on separate days, in a randomized cross-over fashion. Microdialysis probe effluent was collected every 5 rain for ≤ 2.5 h; concentrations of propranolol were determined by liquid scintillation spectroscopy and were corrected for probe recovery of the substrate as determined by in vivo retrodialysis (~ 46%) to estimate aqueous humor concentrations. In separate experiments in rabbits, microdialysis probes were implanted in each eye. ³H-propranolol was administered topically to one eye; the contralateral eye received intracameral ³H-propranolol. Model- independent pharmacokinetic parameters for each treatment phase were calculated. The mean ± S.D. times to peak concentration of propranolol in aqueous humor were 86.6 ± 47.6 min in the dog and 54.1 ± 20.4 rain in the rabbit. The terminal rate constant was 0.0189 ± 0.00429 min^-1 in the dog vs. 0.00983 ± 0.00546 min^-1 in the rabbit. Intraocular tissue availability of propranolol differed markedly between the dog (n = 3) and rabbit (n = 3) (~ 0.056 in the dog vs. ~ 0.55 in the rabbit). These results demonstrate the utility of microdialysis sampling for examination of ocular pharmacokinetics.