TITLE

Electronic and Structural Aspects of P450-Mediated Drug Metabolism

AUTHOR(S)
Lewis, David F. V.; Ito, Yuko; Lake, Brian G.
PUB. DATE
April 2009
SOURCE
Drug Metabolism Letters;Apr2009, Vol. 3 Issue 2, p87
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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.
ACCESSION #
62243549

 

Related Articles

  • Prediction of Human Drug Metabolizing Enzyme Induction. Mankowski, Dayna C.; Ekins, Sean // Current Drug Metabolism;Oct2003, Vol. 4 Issue 5, p381 

    New chemical entities are routinely screened in vitro and in vivo for their ability to induce cytochrome P450s (CYP), other drug-metabolizing enzymes and possibly transporters in an attempt to more accurately predict clinical parameters such as drug-drug interactions and clearance in humans....

  • Editorial. Chandra Prakash // Current Drug Metabolism;Jun2007, Vol. 8 Issue 5, p405 

    The topic of mechanism-based inactivation (MBI) of cytochrome P450 enzymes has been recently emerging as one of ever increasing importance. While our knowledge of some of the biochemistry and chemistry of the phenomenon of MBI of P450 enzymes has been with us for over three decades, the...

  • Effect of tadalafil on cytochrome P450 3A4—mediated clearance: Studies in vitro and in vivo. Ring, Barbara J.; Patterson, Beverley E.; Mitchell, Malcolm I.; Vandenbranden, Mark; Gillespie, Jennifer; Bedding, Alun W.; Jewell, Hayley; Payne, Christopher D.; Forgue, S. Thomas; Eckstein, James; Wrighton, Steven A.; Phillips, Diane L. // Clinical Pharmacology & Therapeutics;Jan2005, Vol. 77 Issue 1, p63 

    Objectives: Tadalafil was examined in vitro and in vivo for its ability to affect human cytochrome P450 (CYP) 3A-mediated metabolism. Methods: Reversible and mechanism-based inhibition of CYP3A by tadalafil was examined in human liver microsomes. The ability of tadalafil to influence CYP3A...

  • Human Cytochromes P450 Associated with the Phase 1 Metabolism of Drugs and other Xenobiotics: A Compilation of Substrates and Inhibitors of the CYP1, CYP2 and CYP3 Families. Lewis, David F.V. // Current Medicinal Chemistry;Oct2003, Vol. 10 Issue 19, p1955 

    This review represents a compilation of typical substrates and inhibitors for human cytochrome P450 (CYP) enzymes that are involved in drug metabolism, specifically those from the CYP1, CYP2 and CYP3 families. Relatively recent literature on substrates and inhibitors has been collected and the...

  • The Effect of Psoralens on Hepatic and Cutaneous Drug Metabolizing Enzymes and Cytochrome P-450. Bickers, David R.; Mukhtar, Hasan; Molica Jr., S. J.; Pathak, Madhu A. // Journal of Investigative Dermatology;Sep82, Vol. 79 Issue 3, p201 

    Psoralens are tricyclic furocoumarins with potent photosensitizing properties in the skin and are now widely used in the treatment of several dermatologic diseases. In this study the effect of 3 different psoralens 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP) and isopsoralen on...

  • Kidney CYP450 Enzymes: Biological Actions Beyond Drug Metabolism. Zhao, X.; Imig, J.D. // Current Drug Metabolism;Feb2003, Vol. 4 Issue 1, p73 

    Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes to 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs), their corresponding dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE). These arachidonic acid metabolites are involved in...

  • Quantitative ADME Proteomics - CYP and UGT Enzymes in the Beagle Dog Liver and Intestine. Heikkinen, Aki; Friedlein, Arno; Matondo, Mariette; Hatley, Oliver; Petsalo, Aleksanteri; Juvonen, Risto; Galetin, Aleksandra; Rostami-Hodjegan, Amin; Aebersold, Ruedi; Lamerz, Jens; Dunkley, Tom; Cutler, Paul; Parrott, Neil // Pharmaceutical Research;Jan2015, Vol. 32 Issue 1, p74 

    Purpose: Beagle dogs are used to study oral pharmacokinetics and guide development of drug formulations for human use. Since mechanistic insight into species differences is needed to translate findings in this species to human, abundances of cytochrome P450 (CYP) and uridine diphosphate...

  • Comparison of Cytochrome P450 2D6 and Variants in Terms of Drug Oxidation Rates and Substrate Inhibition. Niwa, Toshiro; Murayama, Norie; Yamazaki, Hiroshi // Current Drug Metabolism;Jun2011, Vol. 12 Issue 5, p412 

    No abstract available.

  • Atazanavir. Goldsmith, David R.; Perry, Caroline M. // Drugs;2003, Vol. 63 Issue 16, p1679 

    â–´ Atazanavir is a novel azapeptide protease inhibitor with high specificity for, and activity against, HIV-1 protease. â–´ The resistance profile of atazanavir is distinct, with an I50L protease substitution appearing to be the signature mutation. â–´ Atazanavir was not associated...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics