MODELING THE CYTOCHROME P450-MEDIATED METABOLISM OF CHLORINATED VOLATILE ORGANIC-COMPOUNDS

Comparative molecular field analysis (CoMFA), a three-dimensional quan titative structure-activity relationship (BD-QSAR) paradigm, has been used to analyze the metabolic rates, as intrinsic clearance, of a seri es of chlorinated volatile organic compounds (VCCs). A comparison betw een 3D-QSAR and conventional Hansch-type QSAR is provided, To develop predictive 3D-QSARs for metabolism, the standard CoMFA model based on steric and electrostatic potential fields must be supplemented with hy dropathic and molecular orbital information also in the form of three- dimensional fields. A mechanistic interpretation of chlorinated VOC me tabolism by cytochrome P450 isozymes is provided as a rationalization for the inclusion of multiple fields in the CoMFA 3D-QSAR model. Model s of this type have practical utility in the development of generalize d physiologically-based pharmacokinetic models, as well as the rationa l, structure-based, design and/or selection of compounds for use in th e in vivo and in vitro metabolic studies.