Developpement d'approches quantitatives de type 'structure-activite' pour la modelisation pharmacocinetique

Physiologically-based pharmacokinetic (PBPK) models are tools that are useful for predicting the blood and tissue concentrations of a chemical from information on the external dose. The algebraic and differential equations on which PBPK models are based are solved using physiological, physicochemical and biochemical parameters. Whereas information on the value of physiological parameters can be found in the literature for many species, physicochemical and biochemical parameter values for many chemicals are often lacking. This data gap is most often filled by obtaining experimental values using in vivo or in vitro methodologies. However, a more efficient alternative is to directly relate the structure of the compound of interest to the value of these chemical-specific parameters using quantitative structure-activity relationships (QSARs) and chemical structure information. The objective of this study was to develop QSAR methodologies that could be used as tools for simulating the internal concentration of chemicals within different species, so they can be integrated within a risk assessment framework. First, an established QSAR methodology (a Free-Wilson approach that describes chloroethanes) was used within a risk assessment framework. For the first time, a QSAR was used to estimate the internal concentrations corresponding to established safe levels by relating structure to pharmacokinetic parameters. Second, a novel QSAR-PBPK approach that related the structure of chemicals belonging to various families (halomethanes, haloethanes, haloethylenes and aromatic hydrocarbons) to chemical-specific pharmacokinetic parameters was developed and validated in rats. This QSAR-PBPK framework established a structure-PK profile relationship for non steady-state exposure scenarios. Third, this QSAR-PBPK framework was applied to humans by predicting the PK profile using the relationship between structure and human specific PK parameters. Fourth, internal concentrations and PK profiles were extrapolated from one species to another using QSARs specific to the chemical component of each model parameter. Fifth, an approach that directly related chemical structure and steady-state internal concentrations was developed in rats. Sixth, the steady-state concentrations were extrapolated to humans by using the relationships between structure and the underlying parameter involved: the systemic clearance. (Abstract shortened by UMI.)...