57O JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Figure 4. Example of vasoconstriction assay to measure degree of evident blanching caused by various dilutions of corticosteroids when applied (under occlusion) to human skin. The greater the bianchirig, the greater the theoretical potency of the steroid Skin Physiology The obvious interaction desired between drug and skin is for the drug to act on (or in) the skin to produce a desired pharmacologic action. There may simultaneously occur, however, drug-skin interactions which may influence the degree or duration of the pharmacologic action of the drug.

CORTICOII), VEHICLE, AND SKIN INTERACTION 571 Hydration--The drug, by direct or indirect action, could influence the hydration sta,te of the skin which dramatically increases .the per- meability of the skin. A few steroids, such as estrogens and pregneno- lone, have been reported to produce a beneficial effect on aging skin by hydrating the skin. Circttlatory Changes--Tregear (12) has concluded that changes in the cutaneous circulation should have little effect on penetration unless the flow of drug is drastically reduced. The large area of capillary bed availabl.e (1-2 cm2/cm 2 of skin in man) should insure prompt removal if all the capillaries are open. The possibility does exist, however, that agents, such as corticoids, which are potent vasoconstricting agents when applied topically, may slow •their own rate of clearance from the skin. I.ogically, such agents could similarly affect concomitantly administered drugs. Substantivity--When the complex chemical nature of skin is con- sidered, it comes as no surprise that many substances appear to interact strongly with it. These interactions range from weak physical attraction of the van der' Waals type to chemical reactions producing strong chemi- cal bonds. The existence in the skin of a depot or reservoir for topical corticoids has been demonstrated using the return of vasoconstriction after occlusion as a physiological marker. The reservoir was resistant to washing and lasted for up to 16 days (13). Metabolism--In spite of the accessibility of the skin relative to other body organs, very little is known about the metabolism of most drugs by the skin. Fortunately, some studies of hydrocortisone metabolism have been carried out (14). Berliner (5) has made an extensive study on the biotransformation of steroids, especially corticoids, at the target cell level. It was found, in general, that a particular cell type transforms asteroid me!ecule in its own unique way, both quantitatively and quali- tatively. In the case of inflammatory processes, the target cell in ques-. tion is the fibroblast, which is well known to participate very actively in the inflammatory reaction. Tissue culture fibroblasts grown in the presence of fluocinolone acetonide for a 48-hour period are unable to metabolize this steroid, whereas cortisol is metabolized very actively during this same period of time and hence loses its anti-inflammatory ac- tivity. Studies carried out in our own laboratories (15] have also shown that whereas hydrocortisone is rapidly metabolized by rat skin, fluocinolone acetonide and its esters are not, although the esters are hydrolv7ed to yield the parent compound. This inability of the skin to metabolize