Ocular penetration and hypotensive activity of the topically applied carbonic anhydrase inhibitor L-645,151

The effects of the locally active carbonic anhydrase inhibitor L-645,151 on intraocular pressure (IOP), and aqueous humor flow were studied in normotensive albino rabbits, and correlated with the distribution of its hydrolysis product (L-643,799) in ocular tissues. The L-645,151 was given as a suspension in 1% hydroxyethylcellulose, in single drops (50 microliter) of concentrations ranging from 0.06 to 2%. The ocular hypotensive effect showed a distinct dose dependent pattern. At the highest dose, the reduction of pressure was 2.2 +/- 0.4 mmHg (n = 9). Aqueous humor flow was estimated by the IOP recovery rate assay and the changes in ascorbate concentration in aqueous humor. The relative changes in aqueous humor flow displayed a dose dependent pattern. At the highest dose there was a 26-22% decrease, similar to that reported for rabbits in which IOP was raised by intraocular treatment with alpha-chymotrypsin. The concentrations of L-643,799 in ocular tissues were dose related. Representative distribution (microM) for the 2% concentration at peak (1 hr) effect was cornea:290; anterior aqueous 46; posterior aqueous 10; iris + ciliary body 26. The apparent elimination rate constants (A) were: 0.20, 0.19, 0.23 and 0.13 hr-1 respectively. The factors that contribute to the observed high ocular hypotensive potency of L-645,151 include: high lipid solubility of the prodrug; reduced lipid solubility of the drug L-643,799, and accumulation in the cornea; high inhibitory activity against carbonic anhydrase.