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 logP or logD(74)).
Lewis
D F V
DF
School of Biomedical and Life Sciences, University of Surrey, Guildford, GU2 7XH, Surrey, UK. d.lewis@surrey.ac.uk
Dickins
M
M
D000465:Algorithms; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D016208:Databases, Factual; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D008970:Molecular Weight; D000442:Octanols / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012995:Solubility; D012997:Solvents; D014867:Water / Q000737:chemistry; D015262:Xenobiotics / Q000737:chemistry / Q000378:metabolism*
D000442:Octanols; D012997:Solvents; D015262:Xenobiotics; D014867:Water; D003577:Cytochrome P-450 Enzyme System