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Skin Absorption Modeling of Metal Allergens via the Polar Pathway

La Count, Terri D
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397736577

Abstract Details

2014, PhD, University of Cincinnati, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics.
Current predictive algorithms for quantitatively assessing the skin absorption of hydrophilic compounds inadequately describe polar transport. This is due to the general dearth of hydrophilic studies for model development, lack of consensus regarding the actual polar route, and use of theories incongruous with charged substrates. Despite this current state of affairs, polar transport is important, insomuch as both transdermal drug delivery and industrial dermal exposures likely involve ionized materials. To refine the skin absorption model for more accurate polar transport predictions, a two-fold approach was employed. First, various transport parameters for metal salts and polar pathway membrane parameters were characterized using electrical conductance measurements of excised human skin immersed in various concentrations of electrolyte solutions. Measured cation transport numbers augmented this analysis. Results for skin showed cation permselectivity for monovalent ions and effective skin diffusivities greatly reduced over those in solution, with a slight size-dependence demonstrated by the cations. Calculated salt diffusivities aligned with reported nickel and chromium allergenic potentials. Secondly, two theoretical analyses culled from the literature were applied to skin transport. The first analysis accounts for ionic transport across a uniformly charged, homogeneous membrane with an electroneutrality constraint (Schlogl, Z. Phys Chem, 1954). As our interest lies with passive transport across a negatively-charged biomembrane, we limited our analysis to chloride salts, M+z(Cl-)z (z=1,2,3) on the donor side with physiologic saline on the other, but expanded our approach by varying the cationic diffusivity ratio, membrane charge, and cation concentrations. The de-dimensionalized cation flux profiles of each valence were presented as parameterized polynomials and enhancement ratios relative to z:z electrolyte flux in an uncharged membrane. The results revealed that both membrane charge (of any degree) and ion valency play important roles in transport, an effect more pronounced for monovalent cations and thus echoing human skin permselectivity. Calculated fluxes for allergens NiCl2, NiSO4, K2Cr2O7, and CrCl3 using this analysis were within one order of magnitude of both published literature values and available unpublished experimental data. The second analysis quantifies the transport of charged solutes into charged cylindrical pores (Smith and Deen, J Colloid and Interface Science, 1980, 1983), which revealed that substrate charge interactions can dramatically impact solute partitioning. As with the ion valence analysis, the monovalent cation partitioning factors exceeded the polyvalent results. The Schlogl and Smith and Deen analyses overlap with very dilute solutions, whereby the Debye length is sufficient to extend across the pore cross section, yielding a more homogeneously charged membrane. Using these results, a polar pathway route was proposed involving corneocyte and shunt components. Various combinations of permeabilities calculated to assess the impact of an ion valence/charged membrane modifier for corneocyte transport and an electrostatic partitioning factor for lipid defect transport revealed that proposed polar pathway model, with electrostatics based on a slightly charged membrane, adequately predicts the permeabilities of sixteen, hydrophilic permeants investigated. Select predicted lag times and partition coefficients align closely to observed values, features lacking in other models. Future directions include applying the electrostatic analysis to other membranes.
Gerald Kasting, Ph.D. (Committee Chair)
Johannes Nitsche, Ph.D. (Committee Member)
Kevin Li, Ph.D. (Committee Member)
Thomas Ridgway, Ph.D. (Committee Member)
R. Randall Wickett, Ph.D. (Committee Member)
295 p.
Pharmaceuticals
mathematical modeling; skin absorption; metal allergens; polar pathway

Recommended Citations

Citations

  • La Count, T. D. (2014). Skin Absorption Modeling of Metal Allergens via the Polar Pathway [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397736577

    APA Style (7th edition)

  • La Count, Terri. Skin Absorption Modeling of Metal Allergens via the Polar Pathway. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397736577.

    MLA Style (8th edition)

  • La Count, Terri. "Skin Absorption Modeling of Metal Allergens via the Polar Pathway." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397736577

    Chicago Manual of Style (17th edition)

ucin1397736577
451
© 2014, some rights reserved.Creative Commons License Skin Absorption Modeling of Metal Allergens via the Polar Pathway by Terri D La Count is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.