Transscleral diffusion of ethacrynic acid and sodium fluorescein

Cheng Wen Lin, Yong Wang, Pratap Challa, David L. Epstein, Fan Yuan

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Purpose: One of the current limitations in developing novel glaucoma drugs that target the trabecular meshwork (TM) is the induced corneal toxicity from eyedrop formulations. To avoid the corneal toxicity, an alternative approach would be to deliver TM drugs through the sclera. To this end, we quantified ex vivo diffusion coefficient of a potential TM drug, ethacrynic acid (ECA), and investigated mechanisms of ECA transport in the sclera. Methods: An Using-type diffusion apparatus was built to measure the apparent diffusion coefficient of ECA in fresh porcine sclera at 4 °C. To understand mechanisms of ECA transport, we quantified the transscleral transport of a fluorescent tracer, sodium fluorescein (NaF), that has a similar molecular weight but is more hydrophilic compared to ECA. Furthermore, we developed a mathematical model to simulate the transport processes and used it to analyze the experimental data. The model was also used to investigate the dependence of diffusion coefficients on volume fraction of viable cells and the binding of NaF and ECA to scleral tissues. Results: The diffusion coefficients of ECA and NaF in the sclera were 48.5±15.1x10-7 cm2/s (n=9) and 5.23±1.93x10-7 cm2/s (n=8), respectively. Both diffusion coefficients were insensitive to cell shrinkage caused by ECA during the diffusion experiments and cell damage caused by the storage of tissues ex vivo before the experiments. Binding of ECA to scleral tissues could not be detected. The apparent maximum binding capacity and the apparent equilibrium dissociation constant for NaF were 80±5 mM and 2.5±0.5 mM (n=3), respectively. Conclusions: These data demonstrated that ECA diffusion was minimally hindered by structures in the sclera, presumably due to the lack of cells and binding sites for ECA in the sclera.

Original languageEnglish (US)
Pages (from-to)243-251
Number of pages9
JournalMolecular vision
Volume13
StatePublished - Feb 22 2007

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Ethacrynic Acid
Fluorescein
Sclera
Trabecular Meshwork
Pharmaceutical Preparations
Ophthalmic Solutions
Glaucoma
Theoretical Models
Swine
Molecular Weight

All Science Journal Classification (ASJC) codes

  • Ophthalmology

Cite this

Lin, C. W., Wang, Y., Challa, P., Epstein, D. L., & Yuan, F. (2007). Transscleral diffusion of ethacrynic acid and sodium fluorescein. Molecular vision, 13, 243-251.
Lin, Cheng Wen ; Wang, Yong ; Challa, Pratap ; Epstein, David L. ; Yuan, Fan. / Transscleral diffusion of ethacrynic acid and sodium fluorescein. In: Molecular vision. 2007 ; Vol. 13. pp. 243-251.
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Lin, CW, Wang, Y, Challa, P, Epstein, DL & Yuan, F 2007, 'Transscleral diffusion of ethacrynic acid and sodium fluorescein', Molecular vision, vol. 13, pp. 243-251.

Transscleral diffusion of ethacrynic acid and sodium fluorescein. / Lin, Cheng Wen; Wang, Yong; Challa, Pratap; Epstein, David L.; Yuan, Fan.

In: Molecular vision, Vol. 13, 22.02.2007, p. 243-251.

Research output: Contribution to journalArticle

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N2 - Purpose: One of the current limitations in developing novel glaucoma drugs that target the trabecular meshwork (TM) is the induced corneal toxicity from eyedrop formulations. To avoid the corneal toxicity, an alternative approach would be to deliver TM drugs through the sclera. To this end, we quantified ex vivo diffusion coefficient of a potential TM drug, ethacrynic acid (ECA), and investigated mechanisms of ECA transport in the sclera. Methods: An Using-type diffusion apparatus was built to measure the apparent diffusion coefficient of ECA in fresh porcine sclera at 4 °C. To understand mechanisms of ECA transport, we quantified the transscleral transport of a fluorescent tracer, sodium fluorescein (NaF), that has a similar molecular weight but is more hydrophilic compared to ECA. Furthermore, we developed a mathematical model to simulate the transport processes and used it to analyze the experimental data. The model was also used to investigate the dependence of diffusion coefficients on volume fraction of viable cells and the binding of NaF and ECA to scleral tissues. Results: The diffusion coefficients of ECA and NaF in the sclera were 48.5±15.1x10-7 cm2/s (n=9) and 5.23±1.93x10-7 cm2/s (n=8), respectively. Both diffusion coefficients were insensitive to cell shrinkage caused by ECA during the diffusion experiments and cell damage caused by the storage of tissues ex vivo before the experiments. Binding of ECA to scleral tissues could not be detected. The apparent maximum binding capacity and the apparent equilibrium dissociation constant for NaF were 80±5 mM and 2.5±0.5 mM (n=3), respectively. Conclusions: These data demonstrated that ECA diffusion was minimally hindered by structures in the sclera, presumably due to the lack of cells and binding sites for ECA in the sclera.

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Lin CW, Wang Y, Challa P, Epstein DL, Yuan F. Transscleral diffusion of ethacrynic acid and sodium fluorescein. Molecular vision. 2007 Feb 22;13:243-251.