Role of transporters in ocular drug delivery system.

A number of sight threatening diseases affect the anterior and posterior segments of the eye. Various therapeutic agents have been discovered to treat these disorders, but the challenge still lies in effectively delivering these drugs to the eye, primarily due to the unique anatomy and physiology of the ocular structures. Topical mode of administration is the most preferred and convenient delivery method, but ocular bioavailability of most topically applied drugs is less than 5%. Drug loss is primarily due to precorneal factors such as solution drainage, blinking, tear turnover rate and absorption by adjacent tissues i.e., conjunctiva, resulting in the loss of drug to systemic circulation. Low ocular bioavailability has also been attributed to the lipoidal nature of the corneal epithelium and the water-laden stroma which act as rate limiting barriers for hydrophilic and lipophilic molecules, respectively. In addition, the physicochemical properties of the drug itself limit its permeability across ocular barriers. Recently, transporter-targeted prodrug approach has received significant attention and a number of membrane transporters have been discovered in various ocular tissues such as cornea, conjunctiva and retina. These transporters are involved in the translocation of essential nutrients and xenobiotics across biological membranes. Ocular transporters include carriers for peptides, amino acids, glucose, lactate and nucleosides/nucleobases and are primarily localized on the epithelia of cornea, conjunctiva and retina. Prodrugs or analogues designed to target these transporters can significantly enhance the absorption of poorly permeating parent drug. Both solubility and membrane permeability can be improved by proper selection of the promoiety. These prodrugs are recognized by the membrane transporters as substrates and are translocated across the epithelia. Subsequently, the prodrugs are enzymatically cleaved to release the parent drug and the ligand which in most cases is a nutrient and thereby non-toxic. Amongst various nutrient transporters that are expressed on the corneal epithelium, the peptide and amino acid transporters have been classified as high capacity low affinity transporters. The current theme section contains an article, which deals with improving the corneal permeability of a poorly permeable hydrophilic drug, acyclovir (ACV), for the treatment of herpetic keratitis, by chemically derivatizing it into a prodrug (L-aspartate-acyclovir, L-Asp-ACV). L-Asp-ACV was shown to be a substrate of the corneal B 0,+ amino acid transporter and it resulted in a fourfold increase in the transcorneal permeability of ACV. However, D-Asp-ACV did not increase the corneal permeability relative to ACV, suggesting that the L-form of the amino acid is necessary for transporter recognition. Hence, targeting such nutrient transporters on the corneal epithelium is a viable strategy to enhance corneal permeability of hydrophilic therapeutic agents (1). In addition to the tight junctions expressed by the corneal epithelium, more recently, efflux pumps such as P-glycoprotein (P-gp) have also shown to play a role in restricting ocular