title: Prodrug approach to improve absorption of prednisolone.
abstract: Amino acid and dipeptide prodrugs have been developed to examine their potential in enhancing aqueous solubility and permeability as well as to bypass P-glycoprotein (P-gp) mediated cellular efflux of prednisolone. Prodrugs have been synthesized and identified with LC/MS/MS and NMR. Prodrugs displayed significantly higher aqueous solubility relative to prednisolone. These compounds also exhibited higher stability under acidic conditions relative to basic medium. [14]-Erythromycin uptake remained unaltered in the presence of valine-valine-prednisolone (VVP) indicating lower affinity toward P-gp. Moreover, VVP generated significantly higher transepithelial permeability across MDCK-MDR1 cells compared to prednisolone. Importantly, [3H]-GlySar uptake diminished significantly in the presence of VVP indicating high affinity toward peptide transporters. Moreover, prednisolone was regenerated from VVP due to enzymatic hydrolysis in SIRC cell homogenate. Results obtained from these studies clearly suggest that peptide transporter targeted prodrugs is a viable strategy to improve aqueous solubility and overcome P-gp mediated cellular efflux of prednisolone.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Pal
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA. Electronic address: mitraa@umkc.edu.
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001693:Biological Transport, Active; D002460:Cell Line; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D007408:Intestinal Absorption / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D009682:Magnetic Resonance Spectroscopy; D011239:Prednisolone / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D011355:Prodrugs; D012995:Solubility; D014633:Valine / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000893:Anti-Inflammatory Agents; D011355:Prodrugs; D011239:Prednisolone; D014633:Valine
keywords: Efflux; Homogenate; Peptide transporters; Prednisolone; Prodrugs