Factors influencing rates and clearance in P450-mediated reactions: QSARs for substrates of the xenobiotic-metabolizing hepatic microsomal P450s

Various contributory factors associated with the kinetics of cytochrome P450-mediated catalytic activity and the metabolic clearance of drug substrates are discussed and evaluated, based on literature data and physicochemical parameters. Quantitative relationships between molecular structure and biological activity for several series of P450 substrates are presented which point to certain commonalities in P450-catalyzed reactions. In particular. it appears that frontier orbital energies are especially important for the estimation of reaction rates and clearance for many P450 substrates, although occasionally these have to be combined with other descriptors, such as compound lipophilicity (in the form of log P or log D-74). (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.