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Development of a Human Physiologically Based Pharmacokinetics (PBPK) Model For Dermal Permeability for Lindane
Citation:
Sawyer, M., Marina V. Evans, C. Wilson, L. Beesley, L. Leon, C. Eklund, E. Croom, AND R. Pegram. Development of a Human Physiologically Based Pharmacokinetics (PBPK) Model For Dermal Permeability for Lindane. TOXICOLOGY LETTERS. Elsevier Science Ltd, New York, NY, 14(245):pp106-109, (2016).
Impact/Purpose:
The Agency is interested in using in vitro approaches to increase efficiency and reduce the number of animals used in experimentation. The interest in using in vitro data for modeling has become an extension of this approach. The scientific question becomes: is the in vitro data able to provide enough information to complete an in vivo physiological computation? The question can only be answered with a direct comparison of in vitro and in vivo kinetic datasets for a case chemical. Lindane was chosen for this study, since it is still used as a pharmacological agent, and kinetic studies were available for a comparison. The research described in this article demonstrated that in vitro simulations were not affected by the physiological structure of the model. That is, in vivo data was necessary to include all physiological components of the dermal compartment.
Description:
Lindane is a neurotoxicant used for the treatment of lice and scabies present on human skin. Due to its pharmaceutical application, an extensive pharmacokinetic database exists in humans. Mathematical diffusion models allow for calculation of lindane skin permeability coefficients using human kinetic data obtained from in vitro and in vivo experimentation as well as a default compound-specific calculation based on physicochemical characteristics used in the absence of kinetic data. A dermal model was developed to describe lindane diffusion into the skin, where theskin compartment consisted of homogeneous dermal tissue. This study utilized Fick's law of diffusion along with chemical binding to protein and lipids to determine appropriate dermal absorption parameters which were then incorporated into a physiologically based pharmacokinetic (PBPK) model to describe in vivo kinetics. The estimation of permeability coefficients using chemical binding in combination with in vivo data demonstrates the advantages of combining physiochemical properties with a PBPK model to predict dermal absorption.
