Nepafenac, a Unique Nonsteroidal Prodrug with Potential Utility in the Treatment of Trauma-Induced Ocular Inflammation: II. In Vitro Bioactivation and Permeation of External Ocular Barriers

Abstract

Nepafenac, the amide analog of the NSAID amfenac, was examined in vitro for its bioactivation by ocular tissue components and its ability to permeate external ocular barriers. Rabbit tissues catalyzed a concentration-dependent conversion of nepafenac to amfenac. The order of specific hydrolytic activity is retina/choroid ≫ iris/ciliary body. Corneal tissue showed only minimal activity. Similarly, in human ocular cadaver tissue the specific activity of iris/ciliary body was greater than cornea. Continued perfusion of the corneal epithelium demonstrated a nearly six-fold greater permeation coefficient for nepafenac (k _p = 727 × 10⁻⁶ min⁻¹) than for diclofenac (k _p = 127 × 10⁻⁶ min⁻¹). Superior permeation of conjunctival and scleral tissue by nepafenac (k _p = 128 × 10⁻⁶ min⁻¹) compared to diclofenac (k _p = 80 × 10⁻⁶ min⁻¹) was also evident. Short term perfusion (5 min) of the corneal surface with 0.1% nepafenac resulted in sustained flux of drug across the cornea for 6 h. Under identical conditions only 3.3 μM of diclofenac accumulated on the corneal endothelial side compared to 16.7 μM nepafenac. The enhanced permeability of nepafenac, combined with rapid bioactivation to amfenac by the iris/ciliary body and retina/choroid, make it a target specific NSAID for inhibiting prostaglandin formation in the anterior and posterior segments of the eye.