Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation.
A series of stereoisomeric prodrugs have been designed to examine efficacy in generating higher corneal absorption relative to prednisolone. Prodrugs have been studied and identified with LC/MS/MS and NMR analyses. Prodrugs have been characterized for aqueous solubility, buffer stability, and cytotoxicity. 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 higher aqueous solubility relative to prednisolone. Prodrugs circumvented P-gp-mediated cellular efflux and were recognized by peptide transporters. Prodrugs (DP, DDP) produced with D-isomers (D-valine) were significantly stable against both chemical and enzymatic hydrolyses. The order of degradation rate constants observed in chemical and enzymatic hydrolyses were in the same order, i.e., L-valine-L-valine-prednisolone (LLP) > L-valine-D-valine-prednisolone (LDP) > D-valine-L-valine-prednisolone (DLP) > D-valine-D-valine-prednisolone (DDP). Results obtained from this study clearly suggest that stereoisomeric prodrug approach is an effective strategy to overcome P-gp-mediated efflux and improve transcorneal permeability of prednisolone following topical administration.
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri, 64108, USA.
Ye
Y
Sheng
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri, 64108, USA.
Xiaoyan
X
Yang
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri, 64108, USA.
Zhiying
Z
Wang
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri, 64108, USA. mitraa@umkc.edu.
Ashim K
AK
Mitra
D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods; D003315:Cornea / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D013058:Mass Spectrometry / Q000379:methods; D011239:Prednisolone / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism*; D011817:Rabbits; D013237:Stereoisomerism
D011355:Prodrugs; D011239:Prednisolone
Homogenate; P-gp; Prednisolone; Prodrugs; SIRC; Stereoisomeric; Transport