Improved Estimation of Transport Parameters in the Dermis

Improved Estimation of Transport Parameters in the Dermis

Bibliographic Details
Main Author: Ibrahim, Rania
Language:English
Published: University of Cincinnati / OhioLINK 2012
Subjects:
Pharmaceuticals
Transport Parameters
Dermal Clearance
Mathematical Modeling
Dermis
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353951749
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin13539517492021-08-03T05:20:49Z Improved Estimation of Transport Parameters in the Dermis Ibrahim, Rania Pharmaceuticals Transport Parameters Dermal Clearance Mathematical Modeling Dermis <p>An improved model of dermal concentrations and clearance is presented. This was accomplished by refining the assumptions in the current computational model and by developing and analyzing additional data. Accurate values of partition and diffusion coefficients within the lower skin layers are among the information required in order to estimate skin concentrations of permeants following topical application. For highly lipophilic compounds these parameters also play a significant role in determining systemic absorption rates. A modified in vitro experimental methodology was employed to measure the transport parameters of 3 solutes varying in lipophilicity, namely, DEET, diclofenac and parathion. Isolated human dermis obtained from surgical reduction was mounted in side-by-side diffusion cells in the presence and absence of a dialysis membrane (5000 MW cutoff) placed between the dermis and the donor solution. The results indicate that for permeants such as diclofenac and parathion, that are more than about 87% bound to soluble proteins in the dermis, the dialysis membrane method is important in order to obtain accurate estimates of transport and partitioning parameters in dermis.</p><p>A computational model for estimating dermal clearance in humans of arbitrary, non metabolized solutes was developed. The blood capillary component employed slit theory with contributions from both small (10 nm) and large (50 nm) slits. The lymphatic component was derived from previously reported clearance measurements of dermal and subcutaneous injections of 131I-albumin in humans. Model parameters were fit to both blood capillary permeability data and lymphatic clearance data. Small molecules are cleared largely by the blood and large molecules by the lymph. The combined model showed a crossover behavior at approximately 29 kDa, in acceptable agreement with the reported value of 16 kDa. When combined with existing models for stratum corneum permeability and appropriate measures of tissue binding, the developed model has the potential to significantly improve tissue concentration estimates for large or highly protein bound permeants following dermal exposure.</p><p>The dermal clearance model combined with existing models for stratum corneum permeability and appropriate measures of protein binding were used to analyze in vivo concentration data from the literature and compare it to predictions made by the current mathematical model. All data were analyzed using the modified mathematical model; however, for permeants with reported absorption data, a curve-fitting spreadsheet was also used which took into account both skin concentration profiles and absorption profiles in urine. For most permeants the model predicted a steeper slope and hence a quicker decrease in the skin concentration with depth than the observed data. Acceptable predictions were made for Econazole, Methoxsalen, Flurbiprofen and ketoprofen with adjustments to the diffusivity of the stratum corneum. The revised computational model is able to make predictions for topically applied permeants, yet further work can be done to better improve the predictive capability of the model.</p> 2012 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353951749 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353951749 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Pharmaceuticals
Transport Parameters
Dermal Clearance
Mathematical Modeling
Dermis
spellingShingle Pharmaceuticals
Transport Parameters
Dermal Clearance
Mathematical Modeling
Dermis
Ibrahim, Rania
Improved Estimation of Transport Parameters in the Dermis
author Ibrahim, Rania
author_facet Ibrahim, Rania
author_sort Ibrahim, Rania
title Improved Estimation of Transport Parameters in the Dermis
title_short Improved Estimation of Transport Parameters in the Dermis
title_full Improved Estimation of Transport Parameters in the Dermis
title_fullStr Improved Estimation of Transport Parameters in the Dermis
title_full_unstemmed Improved Estimation of Transport Parameters in the Dermis
title_sort improved estimation of transport parameters in the dermis
publisher University of Cincinnati / OhioLINK
publishDate 2012
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353951749
work_keys_str_mv AT ibrahimrania improvedestimationoftransportparametersinthedermis
_version_ 1719418927941943296

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