title: Assessment of penetrant and vehicle mixture properties on transdermal permeability using a mixed effect pharmacokinetic model of ex vivo porcine skin.
abstract: The accurate prediction of the rate and extent of transdermal absorption from topical exposure to chemical mixtures would be beneficial in risk assessment and drug delivery applications. The isolated perfused porcine skin flap (IPPSF) has been used as an ex vivo model for assessing transdermal absorption from topical exposures. A mixed effect, pharmacokinetic tissue model was used to model finite dose, transdermal, absorption data from IPPSF experiments for 12 penetrants dosed in up to 10 different vehicles. The model was able to identify permeability constant, while accounting for between and within unit variability, across the entire data set. This approach provides a platform for exploring the relationship between covariates (chemical descriptors and functions thereof) and the model parameters. Successive models were employed that reduced the overall variability in the parameter estimate by modeling the parameters as functions of the covariates. Log kpwas initially modeled as a function of LogP and MW of the pure penetrant (adjusted r2= 0.48). The addition of mixture factors to account for the different dosing vehicles further improved the relationship: to r2= 0.56 with Connolly molecular area (CMA) and r2= 0.78 with the further addition of total polar surface area difference (TPSAd). The pharmacokinetic model and quantitative structure property relationship (QSPR) developed for the IPPSF may be relevant to clinical transdermal formulation development. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Center for Chemical Toxicology Research and Pharmacokinetics, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA. jt_chittenden@yahoo.com.
authors.forename: Jason T
authors.identifier: http://orcid.org/0000-0002-0195-0855
authors.initials: JT
authors.lastname: Chittenden
authors.affiliation: Institute of Computational Comparative Medicine, Mosier P200A, Kansas State University, Manhattan, KS, 66506-5802, USA.
authors.forename: Jim E
authors.initials: JE
authors.lastname: Riviere
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine
chemical_list: D004364:Pharmaceutical Preparations
keywords: ex vivo; mixed-effect model; quantitative structure property relationship; transdermal permeability; vehicle mixture