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Distributed diffusion-clearance model for transient drug distribution within the skin.

Authors
Kretsos-K; Kasting-GB; Nitsche-JM
Source
J Pharm Sci 2004 Nov; 93(11):2820-2835
NIOSHTIC No.
20029143
Abstract
Quantitative predictions of molecular transport rates through the skin are key to the development of topically applied and transdermally delivered drugs, as well as risk assessment associated with dermal exposure. Most research to date has focused on correlations for the permeability of the stratum corneum, and transient diffusion models that oversimplify vascular clearance processes in terms of a perfect-removal boundary condition at an artificially introduced lower boundary. Considerations of the spatially distributed nature and action of blood vessels have usually been limited to the steady-state case. This article describes a more comprehensive transient model of percutaneous absorption formulated in terms of volumetric dispersion and clearance coefficients reflecting the spatial distribution of vascular processes. The model was implemented through an analysis of published experimental results on in vivo permeation of salicylic acid (SA) in de-epidermized rat skin. With regard to the characterization of SA in rat dermis ("de") in vivo, it was found that: (i) SA is likely to have a dermal effective partition coefficient (relative to pH 7.4 aqueous buffer "pH7.4") around unity (K(de/pH7.4) = 0.9 +/- 0.3); (ii) vascular processes seem not to increase drug dispersion significantly beyond molecular diffusion [D(de) approximately (D(de))(mol) = (8 +/- 3) . 10(-7) cm(2) s(-1)]; and (iii) vascular clearance is characterized by a rate coefficient k(de) = (7 +/- 2) . 10(-4) s(-1). Application of a whole-skin variant of the model (including the stratum corneum and viable epidermis) allowed realistic predictions to be made of transient subsurface concentration levels after application from a finite dose.
Keywords
Physiology; Models; Skin; Skin-exposure; Computer-models; Blood-vessels; Lymphatic-system
Contact
Department of Chemical and Biological Engineering, State University of New York, University at Buffalo, Furnas Hall, Buffalo, New York 14260-4200, USA
CODEN
JPMSAE
Publication Date
20041101
Document Type
Journal Article
Funding Type
Grant
Fiscal Year
2005
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-007529
Issue of Publication
11
ISSN
0022-3549
Priority Area
Research Tools and Approaches: Exposure Assessment Methods
Source Name
Journal of Pharmaceutical Sciences
State
NY; OH
Performing Organization
University of Cincinnati
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