An innovative method to determine percutaneous absorption: Real-time breath analysis and physiologically based pharmacokinetic modeling

From the 1950s through the 1970s, the rate of uptake of a chemical through the skin was generally estimated from studies of humans using radiolabeled compounds (1). More recently, estimates of dermal absorption have been made using animal (in vivo or in vitro) or human (in vitro) skin. In vivo percutaneous absorption in animals is usually determined by measuring radioactivity in blood and excreta following a topical application of the labeled compound. This indirect method of determining percutaneous absorption provides an estimate of the total absorbed dose, but often fails to reveal information on absorption kinetics. To date, the only way to determine the absolute bioavailability of a topically applied compound is to compare the concentrations in blood or urine following topical and intravenous administration (2). Since blood levels may be very low in these situations, this practice is often restricted by the sensitivity limits of the assay or analysis. As an alternative to conducting radiotracer studies, a new, real-time breath analysis system coupled with physiologically based pharmacokinetic (PBPK) modeling has been developed to determine percutaneous absorption in rats and humans in vivo (3). With this system, a topical dose of a compound can be applied to a specified skin surface area, and the breath analysis system can be used to monitor the concentration of that compound and/or its metabolites in the exhaled breath. A PBPK model, modified to describe the dermal exposure, can than be used to determine the skin permeability constant under various exposure situations.