title: Molecular structure-based prediction of human abdominal skin permeability coefficients for several organic compounds.
abstract: Mechanistically based predictions of skin permeability coefficients (Kp) derived solely on the basis of molecular structure information of organic compounds have not been reported previously. The objective of the present study was to predict the human abdominal Kp of structurally unrelated organic compounds using a mechanistic equation that takes into account compound-specific and species-specific determinants of Kp and relates the compound-specific determinants directly to molecular structure information. The method consisted of obtaining predictions based on a modified form of the conventional equation used to describe Kp (= P x D/L, where P, D, and L represent the stratum corneum:water partition coefficient, diffusion coefficient, and path length of diffusion). The value of P was predicted from the n-octanol:water partition coefficient (Po:w) computed from molecular structure information as well as the lipid, protein, and water contents in stratum corneum. The value of D was predicted according to the conventional Einstein-Stoke equation using the molar volume (Vmolar) of compounds computed from molecular structure information as well as data on viscosity of the stratum corneum components. Finally, the value of L was estimated in accordance with the characteristics of the diffusion pathways in the stratum corneum (i.e., transcellular and intercellular pathways). The average ratio of predicted Kp to the corresponding mean experimental values obtained from the literature was 1.25 (SD = 0.68, r = .95) for 47 structurally unrelated organic compounds (volatile organics and drugs), which were characterized by the presence of less than 2 hydrogen bonding groups and Vmolar < 231 cm3/mol. The present study is the first initiative that permits prediction of the human Kp of organic compounds by using molecular structure information as the sole chemical-specific input in a mechanistic equation.
authors.affiliation: Groupe de Recherche en Toxicologie Humaine (TOXHUM), Université de Montréal, Canada. patrick.poulin@roche.com
authors.forename: P
authors.initials: P
authors.lastname: Poulin
authors.forename: K
authors.initials: K
authors.lastname: Krishnan
mesh_terms: D000005:Abdomen; D000438:Alcohols / Q000737:chemistry / Q000493:pharmacokinetics; D002264:Carboxylic Acids / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry / Q000493:pharmacokinetics; D006860:Hydrogen Bonding; D008954:Models, Biological; D009930:Organic Chemicals / Q000737:chemistry* / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption / Q000502:physiology*; D012995:Solubility; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D000438:Alcohols; D002264:Carboxylic Acids; D006838:Hydrocarbons; D009930:Organic Chemicals