RETRACTION: Immunohistochemical and Functional Characterization of Peptide, Organic Cation, Neutral and Basic Amino Acid, and Monocarboxylate Drug Transporters in Human Ocular Tissues

Kadam, Rajendra S.; Vooturi, Sunil K.; Kompella, Uday B.

doi:10.1124/dmd.112.045674

Cited by 11 publications

(13 citation statements)

References 37 publications

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“…Our recent study in human ocular tissues showed the expression and activity of PEPT, OCT, ATB 0,+ , and MCT transporters in cornea as well as retinal pigmented epithelium (RPE) 62 . Although the mRNA expression is responsible for protein expression and activity, there are many instances in which mRNA levels show poor correlation with protein levels 63 .…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Alters Ocular Drug Transporter Expression and Activity in Rat and Calf Models: Implications for Drug Delivery

Kadam¹,

Ramamoorthy

LaFlamme

et al. 2013

Mol. Pharmaceutics

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Purpose Chronic hypoxia, a key stimulus for neovascularization, has been implicated in the pathology of proliferative diabetic retinopathy, retinopathy of prematurity and wet age related macular degeneration. The aim of the present study was to determine the effect of chronic hypoxia on drug transporter mRNA expression and activity in ocular barriers. Methods Sprague Dawley rats were exposed to hypobaric hypoxia (PB = 380 mm Hg) for 6 weeks and neonatal calves were maintained under hypobaric hypoxia (PB = 445 mm Hg) for 2 weeks. Age matched controls for rats and calves were maintained at ambient altitude and normoxia. The effect of hypoxia on transporter expression was analyzed by qRT-PCR analysis of transporter mRNA expression in hypoxic and control rat choroid-retina. Effect of hypoxia on the activity of PEPT, OCT, ATB0+, and MCT transporters was evaluated using in vitro transport studies of model transporter substrates across calf cornea and sclera-choroid-RPE (SCRPE). Results Quantitative gene expression analysis of 84 transporters in rat choroid-retina showed that 29 transporter genes were up regulated or down regulated by ≥1.5-fold in hypoxia. Nine ATP binding cassette (ABC) families of efflux transporters including MRP3, MRP4, MRP5, MRP6, MRP7, Abca17, Abc2, Abc3, and RGD1562128 were up regulated. For solute carrier family transporters, 11 transporters including SLC10a1, SLC16a3, SLC22a7, SLC22a8, SLC29a1, SLC29a2, SLC2a1, SLC3a2, SLC5a4, SLC7a11, and SLC7a4 were up regulated, while 4 transporters including SLC22a2, SLC22a9, SLC28a1, and SLC7a9 were down regulated in hypoxia. Of the 3 aquaporin (Aqp) water channels, Aqp-9 was down regulated and Aqp-1 was up regulated during hypoxia. Gene expression analysis showed down regulation of OCT-1, OCT-2, and ATB0+ and up regulation of MCT-3 in hypoxic rat choroid-retina, without any effect on the expression of PEPT-1 and PEPT-2 expression. Functional activity assays of PEPT, OCT, ATB0+, and MCT transporters in calf ocular tissues showed that PEPT, OCT, and ATB0+ functional activity was down regulated, whereas MCT functional activity was up regulated in hypoxic cornea and SCRPE. Gene expression analysis of these transporters in rat tissues was consistent with the functional transport assays except for PEPT transporters. Conclusions Chronic hypoxia results in significant alterations in the mRNA expression and functional activity of solute transporters in ocular tissues.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Alters Ocular Drug Transporter Expression and Activity in Rat and Calf Models: Implications for Drug Delivery

Kadam¹,

Ramamoorthy

LaFlamme

et al. 2013

Mol. Pharmaceutics

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“…Peptide transporters have been reported to be highly expressed on corneal epithelium (Anand and Mitra, 2002; Kadam et al, 2013; Xiang et al, 2009). These transporters can be targeted with prodrugs due to their broad substrate specificity, affinity and capacity.…”

Section: Resultsmentioning

confidence: 99%

“…The structure, function, mechanisms and substrate specificity have been widely explored. Peptide transporters are highly expressed on cornea (Anand and Mitra, 2002; Kadam et al, 2013; Xiang et al, 2009). These transporters have been targeted to improve transcorneal absorption of poorly permeable drugs such as acyclovir (Anand et al, 2006; Anand and Mitra, 2002) and ganciclovir (Gunda et al, 2006; Majumdar et al, 2005) in our laboratory.…”

Section: Introductionmentioning

confidence: 99%

Prodrug approach to improve absorption of prednisolone

Yang

Pal

Mitra

2015

International Journal of Pharmaceutics

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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 towards 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 towards 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.

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“…In addition to efflux pumps, peptide transporters are highly expressed on the apical surface of corneal epithelial cells (21)(22)(23). This influx transporter has been widely targeted to improve corneal drug absorption due to its high affinity, capacity, and broad substrate specificity.…”

Section: Cellular Uptake Studiesmentioning

confidence: 99%

“…Peptide transporters have been widely targeted due to high substrate affinity, capacity, and broad specificity. These influx transporters have been demonstrated to be highly expressed on the apical surface of the corneal epithelium (21)(22)(23). This transporter has previously been targeted with amino acid and dipeptide prodrugs to improve corneal transport of poorly permeable drugs (23)(24)(25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation

2015

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Abstract. 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-gpmediated efflux and improve transcorneal permeability of prednisolone following topical administration.

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RETRACTION: Immunohistochemical and Functional Characterization of Peptide, Organic Cation, Neutral and Basic Amino Acid, and Monocarboxylate Drug Transporters in Human Ocular Tissues

Cited by 11 publications

References 37 publications

Hypoxia Alters Ocular Drug Transporter Expression and Activity in Rat and Calf Models: Implications for Drug Delivery

Hypoxia Alters Ocular Drug Transporter Expression and Activity in Rat and Calf Models: Implications for Drug Delivery

Prodrug approach to improve absorption of prednisolone

Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation

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