Skin penetration from the inside to the outside: A review

The penetration pathways of topically applied substances into the skin have been investigated extensively over the past years. There is a general agreement that the intercellular penetration pathway is of highest importance, followed by the follicular penetration pathway. The intracellular penetration pathway appears to be negligible.By contrast, the inverse penetration pathways of systemically administered substances into the skin or onto the skin surface have not received much attention. As the epidermis does not contain blood vessels, systemically administered substances must use other transport mechanisms for crossing the epidermis, but these are still largely unknown.For a long time, it was assumed that desquamation could provide an explanation for inverse penetration. Substances were thought to reach the basal cell layer from the circulation system via diffusion, and then to be slowly transported towards the skin surface within the keratinizing and cornifying cells. This process of skin renewal is known to take approximately 3–4 weeks, which is in contrast to recent evidence suggesting that systemically administered substances are able to reach the skin within hours of application. This indicates that other explanations must exist for the process of inverse penetration. Theoretical inverse penetration routes include the intercellular, the follicular, and the intracellular routes, as well as transport via the sebaceous glands or via desquamation, as mentioned above.By reviewing the available literature, it could be assessed that lipophilic substances tend to utilize the flow of sebum to the skin surface as an inverse penetration pathway, whereas hydrophilic substances rather reach the skin via the sweat. The results further indicate that the substances penetrate back into the skin after they reach the skin surface, as if applied topically. This is evidenced by the fact that higher concentrations of test substances were found in the stratum corneum in comparison to lower skin layers. While inverse intercellular penetration and the process of desquamation must still be considered as possible inverse penetration pathways, they appear to be of lesser importance.

Section editor:Michael Roberts – School of Medicine, University of Queensland, Australia