The thesis opens with review chapters concerning theoretical and practical aspects of the investigation of
drug contents in the skin. A discussion of the advantages and limitations of the established methods as well as the relatively new sampling method of microdialysis, which is employed in the experimental section, is given. Factors influencing the barrier function of the normal human skin are described as are the alterations in skin barrier function found in diseased and experimentally barrier perturbed skin. The microdialysis technique consists of introducing an ultra thin, semipermeable tube, a so-called probe, in the dermis. The tube is connected to a precision pump, which provides a steady flow of a tissue-compatible fluid through the probe at a very low flow. Smaller molecules in the tissue, among them the non-
protein bound fraction of the
drug content in the extracellular fluid, will passively diffuse across the surface of the membrane and thus enter the flow of the perfusate, which is sampled at regular intervals and analysed. Microdialysis is used for the determination of
drug levels in the skin after topical as well as systemic
drug delivery in the experimental part of the thesis. The method is not applicable to the investigation of all drugs or compounds, as we have shown that it is not feasible to sample highly
protein-bound drugs or very lipophilic drugs by microdialysis without further development of the method. The investigation of
topical drug administration consists of 2 studies of cutaneous penetration of a model
drug,
salicylic acid, initially investigated in hairless rats and subsequently in human volunteers. In both studies, barrier perturbation of the skin was undertaken by physical (removal of the stratum corneum by repeated tape stripping) or chemical (treatment with
acetone) methods or by provocation of irritative
dermatitis (by application of
sodium lauryl sulphate, a
detergent). Prior to the penetration experiment, the barrier damage inflicted was quantified by non-invasive measurements of transepidermal, water loss and
erythema. The penetration of
salicylic acid, applied in an
ethanol solution in chambers glued to the skin in the barrier perturbed areas, was measured by microdialysis sampling of the
drug level in the underlying dermis. At the end of the experiment, probe depth in the dermis and skin thickness were measured by ultrasound scanning. In humans and hairless rats alike, the cutaneous
drug penetration was highly increased in tape stripped skin (157- and 170-fold increased, respectively, in comparison to the penetration in unmodified skin) and in skin with irritative
dermatitis (46- and 80-fold increased). Delipidization by
acetone led to a doubling of the penetration in humans but had no effect on penetration in hairless rats. In both studies a close correlation between the measurements of barrier perturbation by non-invasive methods and the cutaneous
drug penetration in the same area was found. In the human study, the barrier perturbation in the
acetone treated area was not measurable by non-invasive methods, whereas
drug penetration, measured by microdialysis sampling, was significantly increased, indicating that the microdialysis method possesses high sensitivity in the detection and quantification of perturbed skin barrier function. In the human study, a dose-response relationship between the concentration of
detergent used for the induction of
irritant dermatitis and the ensuing increase in
drug penetration across the skin could be demonstrated. In the hairless rat study a correlation between probe depth in the dermis and
drug penetration was found, demonstrating that the more superficially a probe was placed, the earlier it would be reached by the influx of
drug across the skin. Systemic
drug distribution was studied in healthy volunteers following
oral administration of 2 g
acetylsalicylic acid. (ABSTRACT TRUNCATED)