Stereoisomeric Prodrugs to Improve Ocular And Oral Absorption of Prednisolone
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Abstract
The primary objective of this project is to develop stereoisomeric prodrugs such as Lvaline- D-valine-prednisolone (LDP) and D-valine-L-valine-prednisolone (DLP) to improve ocular and oral absorption of prednisolone. These prodrugs have been examined for their interaction with various influx and efflux transporters commonly expressed on corneal and intestinal epithelium. They have been evaluated for their physico-chemical properties such as aqueous solubility and chemical stability. In vivo oral absorption studies in rats have been conducted to study the efficacy of prodrugs in improving prednisolone absorption post oral delivery. LDP and DLP demonstrated higher aqueous solubility relative to prednisolone. Moreover, LDP and DLP prodrugs demonstrated higher potential to overcome P-gp mediated cellular efflux relative to prednisolone. Transepithelial permeability of these prodrugs was significantly higher compared to prednisolone. Moreover, they were recognized by peptide transporters and generated higher transport relative to prednisolone. LDP and DLP were enzymatically more stable and generated lower affinity towards major metabolizing enzymes such as CYP3A4. Affinity of LDP and DLP was significantly lower towards plasma protein compared to prednisolone. Oral absorption of LDP and DLP was significantly higher compared to prednisolone. Results obtained from this project indicate that these stereoisomeric prodrugs are an attractive strategy to improve ocular absorption of prednisolone. Prednisolone is commonly indicated for the treatment of ocular inflammation, allergy and uveitis. Despite high efficacy, ocular bioavailability of prednisolone following topical or systemic administration is limited. Topical administration is commonly preferred to treat anterior ocular disorders. However, prednisolone absorption following topical delivery is highly restricted. Factors resulting in poor ocular bioavailability include rapid tear turover rate, poor permeation across corneal epithelium and drainage to systemic circulation. Moreover, prednisolone is an excellent substrate of P-glycoprotein (P-gp). Prednisolone absorption in posterior ocular tissues such as retina is restricted following topical administration by aqueous humor outflow. Importantly, prednisolone possesses poor aqueous solubility which makes formulations of ophthalmic solutions very tedious. Systemic drug delivery to posterior ocular tissues is a viable option. However, it is required to cross various blood-ocular barriers to reach intraocular tissues. Importantly, P-gp is also expressed on various blood-ocular barriers which may limit prednisolone absorption from systemic circulation. Moreover, following oral administration, prednisolone is required to permeate intestinal membrane and generate higher systemic concentrations for a long duration of time to reach blood ocular barriers. Results that were obtained from this study indicate that LDP and DLP stereoisomeric prodrug strategy is a viable approach to improve ocular and oral absorption of prednisolone.
Table of Contents
Introduction -- Literature review -- Valine based dipeptide prodrug approach to improve corneal absorption of prednisolone -- Cellular uptake and degradation of prodrugs in corneal cells -- Stereoisomeric prodrugs to improve corneal absorption of prednisolone: synthesis and in vitro evaluation -- Determination of dipeptide prodrugs i anterior ocular tissue homogenates by liquid chromatography-tandem mass spectrometry -- Oral pharmacokinetics of stereoisomeric prodrugs of prednisolone -- Summary and recommendations
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Ph.D.