Author: Bu, H.- Z.

Source: Current Drug Metabolism, Volume 7, Number 3, April 2006 , pp. 231-249(19)

Publisher: Bentham Science Publishers

Abstract:

Cytochrome P450 (CYP) enzymes represent a superfamily of hemoproteins that are involved in the metabolism of a wide variety of endogenous and exogenous compounds. For a given CYP enzyme, kinetic properties of a substrate are usually related to substrate lipophilicity (log P or log D7.4). In this review, enzyme kinetic parameters (Km, Vmax, and Vmax/Km) of 215 CYP3A4-mediated metabolic reactions of 113 drugs in human liver microsomes were obtained from the literature, and lipophilicity values of the 113 drugs were calculated using the ACD/Labs 8.0 program. A low degree of Km- or (Vmax/Km)-lipophilicity correlation, but no Vmax-lipophilicity correlation, is exhibited for the CYP3A4-mediated reactions. Overall, Km decreases, but Vmax/Km increases, with increasing substrate lipophilicity, and Vmax appears to be independent of substrate lipophilicity. In other words, a low Km generally confers a high Vmax/Km ratio for a substrate. The degree of lipophilicity-kinetics correlations is related to both reaction types (or reaction mechanisms) and regiochemical positions (or physicochemical properties) of the reaction groups of the substrates. Among the categorized CYP3A4- mediated reactions, the best lipophilicity-kinetics correlation is achieved for carbon hydroxylation, followed by Ndealkylation. No or little lipophilicity-kinetics correlations are seen for N, S-oxidation and other reactions. Within the hydroxylation group, aliphatic hydroxylation shows the best lipophilicity-kinetics correlation while hydroxylation on a carbon atom adjacent to an aromatic ring does not show any lipophilicity-kinetics correlation. The detailed structural and kinetic data sets of the human liver microsomal CYP3A4-mediated reactions represent a specialized database useful for researchers working in the area of structure-metabolism relationship modeling and analysis.

Keywords: P450; CYP3A4; human liver microsomes; lipophilicity; kinetics

Document Type: Research article

DOI: http://dx.doi.org/10.2174/138920006776359329

Affiliations: 1: Department of Pharmacokinetics, Dynamics, and Metabolism, PGRD, San Diego, CA 92121, USA.

Publication date: 2006-04-01

More about this publication?

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

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