Percutaneous absorption in man is a complex multistep process, the understanding of which requires accurate biological characterization coupled with rigorous application of appropriate physical chemistry. The objectives of this project are to respond to the following questions: (1) """"""""Can the kinetics of skin penetration in man be accurately and reliably quantified by careful in vivo and in vitro experimentation?; (2) Can the results of such experiments, using a wide range of penetrants of different physicochemical properties, be analyzed and interpreted by a quantitative, biologically meaningful, description of transdermal absorption?""""""""; and (3) """"""""With the information generated, can successful prediction of skin penetration be made in clinically and environmentally or occupationally relevant situations (e.g. efficacy assessment of dermatologic or transdermal chemotherapy, prediction of risk after dermal exposure)?"""""""" Pharmacokinetics of chemicals absorbed through human skin in vivo will be followed by monitoring plasma levels or urinary excretion rates as a function of time. Kinetic information will also be collected after parenteral dosing to ascertain the systemic elimination profile of the substrate. In vitro techniques using excised human cadaver skin will be employed to determine stratum corneum resistance to chemical penetration. Information from these three categories of experiment will be analyzed with a recently developed (and continually developing) pharmacokinetic simulation, based upon distinct physical processes involved in skin penetration. In this way, the results will be interpreted to yield kinetic parameters which may classify the penetrant chemicals and quantify their residence times at various regions within the skin and within the systemic circulation. The long term significance of this work is: (A) that it will initiate investigations designed to elucidate the best way to measure and interpret the kinetics of percutaneous absorption in man; and (B) that it will enable prediction (i) of the effectiveness of topically applied local or systemic chemotherapy, and (ii) of the potential hazard when cutaneous exposure to toxic materials takes place.
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