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Many products are applied to human skin for local effects in deeper tissues. Animal studies suggest that deep dermal and/or subcutaneous delivery may be facilitated by both dermal diffusion and transport via the cutaneous vasculature. However, the relationship between the extent and pathways of penetration, drug physicochemical properties and deeper tissue physiology is not well understood.

We have used a physiologically based pharmacokinetic model to analyze published human cutaneous microdialysis data, complemented by our own in vitro skin penetration studies. We found that convective blood, lymphatic and interstitial flow led to significant deep tissue concentrations for drugs that are highly plasma protein bound. In such cases, deeper tissue concentrations will occur earlier and may be several orders of magnitude …