A Literature Review of Enzyme Kinetic Parameters for CYP3A4-Mediated Metabolic Reactions of 113 Drugs in Human Liver Microsomes: Structure- Kinetics Relationship Assessment

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 D(7.4)). In this review, enzyme kinetic parameters (K(m), V(max), and V(max)/K(m)) 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 K(m)- or (V(max)/K(m))-lipophilicity correlation, but no V(max)-lipophilicity correlation, is exhibited for the CYP3A4-mediated reactions. Overall, K(m) decreases, but V(max)/K(m) increases, with increasing substrate lipophilicity, and V(max) appears to be independent of substrate lipophilicity. In other words, a low K(m) generally confers a high V(max)/K(m) 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 N-dealkylation. 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.

Characterization of T-5 N-Oxide Formation as the First Highly Selective Measure of CYP3A5 Activity

“…Quality selective substrates exist for all the major drug-metabolizing P450s except CYP3A4 and CYP3A5 (Yuan et al, 2002). This is ironic because these enzymes are involved in the metabolism of more drugs than any other P450 enzyme (Wilkinson, 1996;Thummel and Wilkinson, 1998;Bu, 2006;Niwa et al, 2008). The frequently used CYP3A substrates include testosterone, midazolam, nifedipine, and erythromycin.…”

Selective Mechanism-Based Inactivation of CYP3A4 by CYP3cide (PF-04981517) and Its Utility as an In Vitro Tool for Delineating the Relative Roles of CYP3A4 versus CYP3A5 in the Metabolism of Drugs

“…Such P450 reaction phenotyping experiments have now become standard practice in the evaluation of any new chemical entity believed to be metabolized by the P450 enzymes (Harper and Brassil, 2008;Emoto et al, 2010). Of the P450 enzymes, the CYP3A family is the most abundant and is responsible for the metabolism of a wide range of xenobiotics (Shimada et al, 1994;Wilkinson, 1996;Paine et al, 1997;Thummel and Wilkinson, 1998;Bu, 2006;Niwa et al, 2008). Four members of the family have been reported in humans (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) (Daly, 2006).…”

Scientific Opinion on Flavouring Group Evaluation 67, Revision 1 (FGE.67Rev.1): Consideration of 40 furan-substituted aliphatic hydrocarbons, alcohols, aldehydes, ketones, carboxylic acids and related esters, sulfides, disulfides and ethers evaluated by J

“…up to 1923 -13 220 μg/ml or 20 -150 mmol/l) were used in the study conducted by Stich et al (Stich et al, 1981b). The Km for most enzyme kinetic processes is at or below 100 μmol/l (Bu, 2006;Wang and James, 2006), and thus the high concentrations used in this study may not be relevant to the human condition, especially with respect to the low levels of flavouring agents added to food. Furthermore, no information was available on culture conditions that may have promoted apoptosis.…”