Human Skin Drug Metabolism: Relationships between Methyl Salicylate Metabolism and Esterase Activities in IVPT Skin Membranes

Abstract

The presence of esterase enzymes in human skin and their role in drug metabolism has been reported, but their distribution in the various skin layers and the relative contributions of those layers to metabolism is poorly defined. To gain further insight into esterase distribution, we performed in vitro skin permeation of a commercial 28.3% methyl salicylate (MeSA) cream (Metsal™) in Franz diffusion cells, using a range of human skin membranes, all from the same donor. The membranes were viable epidermis separated by a dispase II enzymatic method, heat separated epidermis, dermatomed skin, and dermis separated by a dispase II enzymatic method. Methyl salicylate and its metabolite, salicylic acid (SA), were measured by high-performance liquid chromatography. Alpha naphthyl acetate and Hematoxylin and Eosin staining provided qualitative estimations of esterase distribution in these membranes. The permeation of methyl salicylate after 24 h was similar across all membranes. Salicylic acid formation and permeation were found to be similar in dermatomed skin and dermis, suggesting dermal esterase activity. These results were supported by the staining studies, which showed strong esterase activity in the dermal–epidermal junction region of the dermis. In contrast with high staining of esterase activity in the stratum corneum and viable epidermis, minimal stained and functional esterase activity was found in heat-separated and dispase II-prepared epidermal membranes. The results are consistent with dispase II digesting hemidesmosomes, penetrating the epidermis, and affecting epidermal esterases but not those in the dermis. Accordingly, whilst the resulting dispase II-generated dermal membranes may be used for in vitro permeation tests (IVPT) involving esterase-based metabolic studies, the dispase II-generated epidermal membranes are not suitable for this purpose.

Hydrogel Microneedles with Programmed Mesophase Transitions for Controlled Drug Delivery

“…These MNs would transform into enzymatically degradable drug eluting hydrogels upon their penetration into the skin and absorption of interstitial fluid, followed by their in situ transition into gel microparticles, which can enhance drug release and be fully degraded by target enzymes into soluble hydrophilic polymers. Herein, as a proof of concept, the triblock polymeric amphiphile is composed of a central hydrophilic poly(ethylene glycol) (PEG, 10 kDa) block conjugated with two hydrophobic dendritic branching units functionalized with ester-based nonyl end-groups (Tri-C9), which can potentially be cleaved by skin esterases 25 ( Figure 1 ), and dexamethasone (DEX) was used as a model drug.…”