Sclera-Choroid-RPE Transport of Eight β-Blockers in Human, Bovine, Porcine, Rabbit, and Rat Models

Kadam, Rajendra S.; Cheruvu, N.; Edelhauser, Henry F.; Kompella, Uday B.

doi:10.1167/iovs.10-6233

Cited by 31 publications

(48 citation statements)

References 27 publications

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“…Likewise, Cruysberg et al (2002) have shown that the transscleral permeability of corticosteroids is related to molecular weight and lipid solubility with tissue transport of the most lipophilic molecule being the least and that of the least lipophilic molecule being the most. Consistent with our ␤-blockers transport studies across sclera-choroid-RPE in various species (Kadam et al, 2011), we observed that hydrophilic corticosteroids were transported better than lipophilic molecules during the course of the study (Figs. 2 and 3).…”

Section: Thakur Et Alsupporting

confidence: 89%

“…The bovine sclera and sclera-choroid-RPE transport study was conducted as described previously Thakur et al, 2010;Kadam et al, 2011). An isotonic assay buffer (pH 7.4) with the following composition was used during the entire tissue isolation procedure and transport study: 122 mM NaCl, 25 mM NaHCO 3 , 1.2 mM MgSO 4 , 0.4 mM K 2 HPO 4 , 1.4 mM CaCl 2 , 10 mM HEPES, and 10 mM glucose.…”

Section: Methodsmentioning

confidence: 99%

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Influence of Drug Solubility and Lipophilicity on Transscleral Retinal Delivery of Six Corticosteroids

Thakur

Kadam²,

Kompella³

2011

Drug Metab Dispos

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ABSTRACT:The influence of drug properties including solubility, lipophilicity, tissue partition coefficients, and in vitro transscleral permeability on ex vivo and in vivo transscleral delivery from corticosteroid suspensions was determined. Solubility, tissue/buffer partition coefficients for bovine sclera and choroid-retinal pigment epithelium (CRPE), and in vitro bovine sclera and sclera-choroid-retinal pigment epithelium (SCRPE) transscleral transport were determined at pH 7.4 for triamcinolone, prednisolone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, and budesonide in solution. Ex vivo and in vivo transscleral delivery was assessed in Brown Norway rats after posterior subconjunctival injection of a 1 mg/ml suspension of each corticosteroid. Corticosteroid solubility and partition coefficients ranged from ϳ17 to 300 g/ml and 3.0 to 11.4 for sclera and from 7.1 to 35.8 for CRPE, respectively, with the more lipophilic molecules partitioning more into both tissues.

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Section: Thakur Et Alsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Influence of Drug Solubility and Lipophilicity on Transscleral Retinal Delivery of Six Corticosteroids

Thakur

Kadam²,

Kompella³

2011

Drug Metab Dispos

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“…In vitro transport studies across human cornea and sclera-choroid-RPE (SCRPE) were carried out according to a previously published method (Kadam et al, 2011) using the cassette dosing approach. A cassette of drug transporter substrates, including Gly-Sar (PEPT), L-tryptophan (ATB 0,+ ), MPP + (OCT), and phenylacetic acid (MCT) at a concentration of 100 mM in assay buffer was prepared.…”

Section: Methodsmentioning

confidence: 99%

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

2012

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Since there is paucity of information on solute transporters in human ocular tissues, the aim of this study was immunohistochemical and functional characterization of peptide transporters (PEPT), organic cation transporters (OCTs), neutral and basic amino acid transporters (ATB 0,+ ), and monocarboxylate transporters (MCTs) in human ocular barriers. Immunohistochemical localization of transporters was achieved using 5-mm-thick paraffin-embedded sections of whole human eyes. In vitro transport studies were carried out across human cornea and sclera-choroid-retinal pigment epithelium (SCRPE) using a cassette of specific substrates in the presence and absence of inhibitors to determine the role of transporters in transtissue solute delivery. Immunohistochemistry showed the expression of PEPT-1, PEPT-2, ATB 0,+

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“…In vitro transport studies were carried out according to previously published method 28 . Due to very low solubilities (< 10 μg/ml) of celecoxib, CMA and CAA in water, 100 μg/ml solutions of these agents were prepared in assay buffer using 5% HPβCD.…”

Section: Methodsmentioning

confidence: 99%

Hydrophilic Prodrug Approach for Reduced Pigment Binding and Enhanced Transscleral Retinal Delivery of Celecoxib

et al. 2012

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Purpose Transscleral retinal delivery of celecoxib, an anti-inflammatory and anti-VEGF agent is restricted by its poor solubility and binding to the melanin pigment in choroid-RPE. The purpose of this study was to develop soluble prodrugs of celecoxib with reduced pigment binding and enhanced retinal delivery. Methods Three hydrophilic amide prodrugs of celecoxib were synthesized and characterized for solubility and lipophilicity. In vitro melanin binding to natural melanin (Sepia Officinalis) was estimated for all three prodrugs. In vitro transport studies across isolated bovine sclera and sclera-choroid-RPE (SCRPE) were performed. Prodrug with the highest permeability across SCRPE was characterized for metabolism and cytotoxicity and its in vivo transscleral delivery in pigmented rats. Results Celecoxib succinamidic acid (CSA), celecoxib maleamidic acid (CMA), and celecoxib acetamide (CAA) were synthesized and characterized. Aqueous solubilities of CSA, CMA, and CAA were 300-, 182-, and 76-fold higher, respectively, than celecoxib. Melanin binding affinity and capacity was significantly lower than celecoxib for all three prodrugs. Rank order for the % in vitro transport across bovine sclera and SCRPE was CSA > CMA ~ CAA ~ celecoxib, with the transport being 8-fold higher for CSA than celecoxib. CSA was further assessed for its metabolic stability and in vivo delivery. CSA showed optimum metabolic stability in all eye tissues with only 10–20 % conversion to parent celecoxib in 30 minutes. Metabolic enzymes responsible for bioconversion included amidases, esterase, and cytochrome P-450. In vivo delivery in pigmented BN rats showed that CSA had 4.7-, 1.4-, 3.3-, 6.0-, and 4.5- fold higher delivery to sclera, choroid-RPE, retina, vitreous, and lens than celecoxib. CSA has no cytotoxicity in ARPE-19 cells in the concentration range of 0.1 to 1000 μM. Conclusions Celecoxib succinamidic acid is a soluble prodrug of celecoxib with reduced melanin binding which enhances transscleral retinal delivery of celecoxib.

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Sclera-Choroid-RPE Transport of Eight β-Blockers in Human, Bovine, Porcine, Rabbit, and Rat Models

Cited by 31 publications

References 27 publications

Influence of Drug Solubility and Lipophilicity on Transscleral Retinal Delivery of Six Corticosteroids

Influence of Drug Solubility and Lipophilicity on Transscleral Retinal Delivery of Six Corticosteroids

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

Hydrophilic Prodrug Approach for Reduced Pigment Binding and Enhanced Transscleral Retinal Delivery of Celecoxib

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