Cl. Waller et al., MODELING THE CYTOCHROME P450-MEDIATED METABOLISM OF CHLORINATED VOLATILE ORGANIC-COMPOUNDS, Drug metabolism and disposition, 24(2), 1996, pp. 203-210
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.