Electronic and structural aspects of p450-mediated drug metabolism.

Lewis, DF, Ito, Y and Lake, BG (2009) Electronic and structural aspects of p450-mediated drug metabolism. Drug Metab Lett, 3 (2). pp. 87-100.

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Abstract

From a consideration of first principles for enzymes kinetics, we have employed theoretical methods which enable one to analyse the kinetics of cytochrome P450-mediated reactions which have been based on the known physicochemical principles underlying the majority of chemical or enzymatic reactions. A comparison is made between the correlation equations produced from the QSAR analysis of experimental P450 reaction rate data and those obtained from first principles, where there appears to be a generally satisfactory concordance between the two procedures. In this respect, we have developed expressions based on standard reaction kinetics theory which incorporate the Eyring and Marcus relationships. The analysis of P450-catalyzed reaction rates is elaborated to encompass a treatment of metabolic clearance, and satisfactory correlations are obtained with literature values for both intrinsic clearance and whole body clearance in terms of compound lipophilicity derived from log P data, where P is the octanol/water partition coefficient. The importance of ionization potential as a factor in the overall catalytic turnover of P450-mediated reactions is noted, especially in combination with the lipophilicity parameter, log P.

Item Type:	Article
Authors :	Name Email ORCID Lewis, DF d.lewis@surrey.ac.uk UNSPECIFIED Ito, Y UNSPECIFIED UNSPECIFIED Lake, BG UNSPECIFIED UNSPECIFIED
Date :	April 2009
Uncontrolled Keywords :	Cytochrome P-450 Enzyme System, Humans, Models, Molecular, Models, Theoretical, Octanols, Pharmaceutical Preparations, Quantitative Structure-Activity Relationship, Water
Related URLs :	Author
Depositing User :	Symplectic Elements
Date Deposited :	17 May 2017 09:34
Last Modified :	17 May 2017 09:34
URI:	http://epubs.surrey.ac.uk/id/eprint/824286

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