Corneal Penetration Behavior of β-Blocking Agents I: Physicochemical Factors

Schoenwald, Ronald D.; Huang, Hong-Shian

doi:10.1002/jps.2600721108

Cited by 396 publications

(34 citation statements)

References 18 publications

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“…In ocular drug delivery, QSPKR type of analysis was attempted to correlate physicochemical properties to drug permeation across cornea (10)(11)(12)(13)(14), conjunctiva (12,15,16), sclera (12), and retinal pigment epithelium (17). Maurice (18,19) was the first to study the QSPKR in vitreous humor.…”

Section: Introductionmentioning

confidence: 99%

Prediction of Vitreal Half-Life Based on Drug Physicochemical Properties: Quantitative Structure–Pharmacokinetic Relationships (QSPKR)

et al. 2008

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Section: Introductionmentioning

confidence: 99%

Prediction of Vitreal Half-Life Based on Drug Physicochemical Properties: Quantitative Structure–Pharmacokinetic Relationships (QSPKR)

et al. 2008

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“…13-18 A number of techniques for studying corneal permeability have been used, including ex vivo corneas mounted in various types of permeability chambers, 19-22 live animal studies, 23-25 and more recently, cell culture based systems. 26-29 Each has its merits, and information gathered from any of the above mentioned techniques can contribute to our understanding of corneal permeability.…”

Section: Resultsmentioning

confidence: 99%

Aliphatic β-Nitroalcohols for Therapeutic Corneoscleral Cross-Linking

Wen

Trokel

Kim

et al. 2013

Cornea

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Introduction Our recent tissue cross-linking studies have raised the possibility of using aliphatic β-nitro alcohols (BNAs) for pharmacologic, therapeutic corneal cross-linking. The present study was performed in order to determine the permeability of BNAs and to explore the use of permeability enhancing agents. Methods Ex vivo rabbit corneas were mounted in a typical Franz diffusion chamber. BNA permeability was determined by assaying the recipient chamber over time using a modification of the Griess nitrite colorimetric assay. The apparent permeability coefficient (Ptot) was determined for 2 mono-nitroalcohols, 2-nitroethanol (2NE) and 2-nitro-1-propanol (2NProp); a nitro-diol (2-methyl-2-nitro-1,3-propanediol=MNPD); and a nitro-triol (2-hydroxymethyl-2-nitro-1,3-propanediol=HNPD). Permeability enhancing effects using benzalkonium chloride (BAC) [0.01 and 0.02%], ethylenediaminetetraacetic acid (EDTA) [0.05%], and a combination of BAC 0.01% + tetracaine (TC) [0.5%] were also studied. Results The Ptot (+/−S.E.) values (cm/sec) were as follows: Ptot=4.33×10−5 (+/−9.82×10−6) for 2NE (MW=91), Ptot=9.34×10−6 (+/− 2.16×10−7) for 2NProp (MW=105), Ptot=4.37×10−6 (+/− 1.86×10−7) for MNPD (MW=135), and Ptot=8.95×10−7 (+/−1.93×10−8) for HNPD (MW=151). Using the nitrodiol, permeability increased approximately two-fold using BAC 0.01%, five-fold using BAC 0.02% and five-fold using the combination of BAC 0.01% + TC 0.5%. No effect was observed using EDTA 0.05%. Conclusions The results indicate that the corneal epithelium is permeable to BNAs with the apparent permeability corresponding to molecular weight. The findings are consistent with previous literature indicating that the small size of these compounds (<10Å) favors their passage through the corneal epithelium via the paracellular route. This information will help to guide dosing regimens for in vivo topical cross-linking studies.

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“…2 Many topically instilled drugs reach the internal segments of the eye through the cornea. 2 As stated by Dey et al (2003), 2 “these drugs include steroids, 31,32 ß-blockers, 33,34 antibiotics, 35,36,37 and nonsteroidal anti-inflammatory agents. 38 ” The cul-de-sac, as a route for topical drug administration, is the most common route of ocular drug delivery.…”

Section: Discussionmentioning

confidence: 99%

Molecular Expression and Functional Evidence of a Drug Efflux Pump (BCRP) in Human Corneal Epithelial Cells

Karla

Earla

Boddu

et al. 2009

Current Eye Research

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Purpose Breast Cancer Resistance Protein (BCRP) belongs to the family of efflux transporters involved in drug efflux leading to drug resistance. The objective of this study was to explore physical barriers for ocular drug absorption and to verify the presence and possible role of BCRP as a bar-rier for ocular drug resistance. Methods Transfected human corneal epithelial cells (SV40-HCEC) were selected as an in vitro model for corneal epithelium with MDCKII-BCRP as positive control. [3H]-Mitoxantrone ([3H]-MTX), which is a proven substrate for organic anion transporter like BCRP, was selected as a model drug for functional expression studies. Fumetremorgin C (FTC), a known specific inhibitor for BCRP and GF120918, an inhibitor for BCRP and P-gp, were added to inhibit BCRP-mediated efflux. PGP-4008, a specific inhibitor of P-gp was used to delineate the contribution of P-gp. The mRNA extracted from cells was used for RT-PCR analysis and gene expression. Membrane fractions of SV40-HCEC and MDCKII-BCRP were used for immunoprecipitation followed by Western blot analysis. Results Efflux was inhibited significantly in the presence of FTC and GF120918. Dose-dependent inhibition of efflux by BCRP was noticed in SV40-HCEC and MDCKII-BCRP in the presence of FTC and GF120918, and the efflux was ATP-dependent. The metabolic inhibitor, 2,4-DNP, significantly inhibited efflux. No pH-dependent efflux was noticed except at pH 5.5. RT-PCR analysis indicated a unique and distinct band at ~429 bp, corresponding to BCRP in SV40-HCEC and MDCKII-BCRP cells. Western Blot analysis indicated a specific band at ~70 kDa in the membrane fraction of SV40-HCEC and MDCKII-BCRP cells. Conclusions We have demonstrated the expression of BCRP in human corneal epithelial cells and, for the first time, demonstrated its functional activity leading to drug efflux. RT-PCR and Western blot analysis further confirmed this finding.

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Corneal Penetration Behavior of β-Blocking Agents I: Physicochemical Factors

Cited by 396 publications

References 18 publications

Prediction of Vitreal Half-Life Based on Drug Physicochemical Properties: Quantitative Structure–Pharmacokinetic Relationships (QSPKR)

Prediction of Vitreal Half-Life Based on Drug Physicochemical Properties: Quantitative Structure–Pharmacokinetic Relationships (QSPKR)

Aliphatic β-Nitroalcohols for Therapeutic Corneoscleral Cross-Linking

Molecular Expression and Functional Evidence of a Drug Efflux Pump (BCRP) in Human Corneal Epithelial Cells

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