Stereoisomeric Prodrugs to Improve Prednisolone Absorption - Abstract
A series of stereoisomeric prodrugs have been designed to examine their efficacy in generating higher absorption relative to prednisolone. Prodrugs have been synthesized and identified with LC/MS/MS and NMR analysis. Prodrugs have been for their aqueous solubility, buffer stability and cell cytotoxicity properties. Cellular uptake and permeability studies have been conducted across MDCK-MDR1 cells to determine prodrug affinity towards P-glycoprotein (P-gp) and peptide transporters. Enzyme-mediated degradation of prodrugs has been determined using Statens Seruminstitut Rabbit Cornea (SIRC) cell homogenates. Prodrugs exhibited superior aqueous solubility relative to prednisolone. Prodrugs circumvented P-gp mediated cellular efflux
and were recognized by peptide transporters. Prodrugs produced with D-isomers (D-valine) were significantly stable towards both chemical and enzymatic hydrolysis. Results obtained from this study clearly suggest that a stereoisomeric prodrug approach is an effective strategy to overcome P-gp mediated efflux and poor transcorneal permeability of prednisolone following topical administration.