The design of efficacious transdermal delivery methods for contraceptives and other drugs of interest requires an understanding of the mechanisms of solute transport through the skin, especially the stratum corneum barrier, and metabolism in the skin. The overall goal of the proposed study is the development of mechanisms of transport and metabolism of steroids in the skin. The goal will be achieved through meeting the following specific aims: 1. OBTAIN AN UNDERSTANDING OF STRUCTURAL ASPECTS OF STRATUM CORNEUM AFFECTING TRANSPORT OF MODEL CONTRACEPTIVE STEROIDS IN SKIN Effect of stratum corneum's chemical and physical structure on the transport of the model solutes through the stratum corneum will be studied under controlled conditions. The effects of hydration, temperature, penetration enhancers and solvents, individually and concomitantly, on the fluidity of lipids and conformation of keratinized proteins within the stratum corneum will be determined. The influence of temperature, hydration, penetration enhancers and solvents on the structure of the stratum corneum and subsequent enhancement of transport of selected contraceptives will be studied. 2. DETERMINE THE EFFECT OF ENVIRONMENTAL FACTORS AND PENETRATION ENHANCERS ON THE PHARMACOKINETICS AND METABOLISM OF MODEL CONTRACEPTIVES IN THE STRATUM CORNEUM The effects of temperature, hydration, penetration enhancers and solvents on the metabolism and pharmacokinetics of selected contraceptive agents will be determined. A diffusional model incorporating the metabolism of the model contraceptives, as well as environmental effects will be developed from coupling the experimental data from Specific Aims 1 and 2. 3. CORRELATION OF IN VITRO AND IN VIVO STUDIES INVOLVING HAIRLESS MOUSE AND HUMAN SKIN The mechanisms of transport and metabolism of the selected contraceptive steroids will be correlated in vitro and then modelled through a diffusional model taking into consideration appropriate metabolism and environmental factors. The model will then be tested in vivo using human skin grafted onto rats (unique rat-flap model developed at the University of Utah by Dr. G. Krueger, Division of Dermatology.)
| Cooper, E A; Knutson, K (1995) Fourier transform infrared spectroscopy investigations of protein structure. Pharm Biotechnol 7:101-43 |
| Goates, C Y; Knutson, K (1994) Enhanced permeation of polar compounds through human epidermis. I. Permeability and membrane structural changes in the presence of short chain alcohols. Biochim Biophys Acta 1195:169-79 |
| Goates, C Y; Knutson, K (1993) Enhanced permeation and stratum corneum structural alterations in the presence of dithiothreitol. Biochim Biophys Acta 1153:289-98 |
| Pershing, L K; Parry, G E; Lambert, L D (1993) Disparity of in vitro and in vivo oleic acid-enhanced beta-estradiol percutaneous absorption across human skin. Pharm Res 10:1745-50 |
