Improved Estimation of Transport Parameters in the 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>

Name thesis:degree_name

PhD

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Pharmacy: Pharmaceutical Sciences/Biopharmaceutics

Grantor dc:publisher

University of Cincinnati

Year dc:date

2012

Author dc:creator

• Ibrahim, Rania

Contributors dc:contributor

• Kasting, Gerald

• Pharmaceuticals
• Transport Parameters
• Dermal Clearance
• Mathematical Modeling
• Dermis

Statement dc:rights

• 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.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353951749

OAI identifier oai:identifier

oai:etd.ohiolink.edu:ucin1353951749