title: Skin solubility determines maximum transepidermal flux for similar size molecules.
abstract: OBJECTIVE
  The maximum flux of solutes penetrating the epidermis has been known to depend predominantly on solute molecular weight. Here we sought to establish the mechanistic dependence of maximum flux on other solute physicochemical parameters.
  
  
  METHODS
  Maximum fluxes, stratum corneum solubilities and estimated diffusivities through human epidermis were therefore determined for 10 phenols with similar molecular weights and hydrogen bonding but varying in lipophilicity.
  
  
  RESULTS
  Maximum flux and stratum corneum solubilities of the phenolic compounds both showed a bilinear dependence on octanol-water partition coefficient (P), with solutes having a maximum solubility in the stratum corneum when 2.7<log P<3.1. In contrast, lag times and diffusivities were relatively independent of P. Stratum corneum-water partition coefficients and epidermal permeability coefficients were consistent with previously reported data.
  
  
  CONCLUSIONS
  A key finding is that the convex dependence of maximum flux on lipophilicity arises primarily from variations in stratum corneum solubility, and not from diffusional or partitioning barrier effects at the stratum corneum-viable epidermis interface for the more lipophilic phenols. Our data support a solute structure-skin transport model for aqueous solutions in which permeation rates depend on both partitioning and diffusivity: partitioning is related to P, and diffusivity to solute size and hydrogen bonding.
authors.affiliation: Therapeutics Research Unit, School of Medicine, Princess Alexandra Hospital, The University of Queensland, Woolloongabba, QLD 4102, Australia.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Grice
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Owen G
authors.initials: OG
authors.lastname: Jepps
authors.forename: Guang-Ji
authors.initials: GJ
authors.lastname: Wang
authors.forename: Michael S
authors.initials: MS
authors.lastname: Roberts
mesh_terms: D006801:Humans; D010539:Permeability; D010599:Pharmacokinetics; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D012995:Solubility