In Vitro Metabolism

Ekins, Sean; Mäenpää, J; Wrighton, Steven

doi:10.1201/b13995-15

Cited by 22 publications

(5 citation statements)

References 165 publications

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“…molecular models for better structure-metabolism relationship analyses of CYP3A4 substrates in humans [9][10][11][12]. Note that the 113 CYP3A4 substrates have a molecular-weight range of 154-1217 amu with a mean ± SD of 409 ± 160 amu.…”

Section: Data Collectionmentioning

confidence: 99%

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

2006

CDM

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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.

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Section: Data Collectionmentioning

confidence: 99%

“…Individual CYP enzymes exhibit unique substrate specificity and regio-and stereoselectivity that reflect different tertiary structures [2][3][4][5][6][7][8][9][10][11][12]. CYP3A4 is particularly important in the metabolism of many classes of drugs because it catalyzes a broad range of metabolic reactions [1,2].…”

Section: Introductionmentioning

confidence: 99%

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

2006

CDM

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“…To date, research predicting drug metabolism has been limited to a number of technologies, such as rule-based tools and algorithms for sites of metabolism [7], electronic models [8,9], homology models [10][11][12], as well as pharmacophores and QSARs for K m values [13][14][15]. In general, the data sets that the QSAR models use are severely limited in both size and structural diversity.…”

Section: Role Of Computational Approaches For Drug Metabolismmentioning

confidence: 99%

In silico approaches to predicting drug metabolism, toxicology and beyond

Ekins

2003

Biochemical Society Transactions

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The discovery and optimization of new drug candidates is becoming increasingly reliant upon the combination of experimental and computational approaches related to drug metabolism, toxicology and general biopharmaceutical properties. With the considerable output of high-throughput assays for cytochrome-P450-mediated drug-drug interactions, metabolic stability and assays for toxicology, we have orders of magnitude more data that will facilitate model building. A recursive partitioning model for human liver microsomal metabolic stability based on over 800 structurally diverse molecules was used to predict molecules with known log in vitro clearance data (Spearman's rho -0.64, P <0.0001). In addition, with solely published data, a quantitative structure-activity relationship for 66 inhibitors of the potassium channel human ether-a-gogo (hERG) that has been implicated in the failure of a number of recent drugs has been generated. This model has been validated with further published data for 25 molecules (Spearman's rho 0.83, P <0.0001). If continued value is to be realized from these types of computational models, there needs to be some applied research on their validation and optimization with new data. Some relatively simple approaches may have value when it comes to combining data from multiple models in order to improve and focus drug discovery on the molecules most likely to succeed.

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“…For QSAR, 3D-molecular descriptors were found to be necessary [98]. Preliminary 3D-QSAR pharmacophore models to predict substrates and inhibitors of CYP2C9, 2D6, and 3A4 have been published [99,100,101]. Though they show poor predictive power, they have helped to identify problem areas such as the quality of data used to make the models, and that most available modeling software cannot cope with the chemical diversity encountered when dealing with the substrates or inhibitors of a specific CYP.…”

Section: Reporter Gene Systemsmentioning

confidence: 99%

In Vitro High Throughput Screening of Compounds for Favorable Metabolic Properties in Drug Discovery.

Masimirembwa¹,

Thompson²,

Andersson

2001

CCHTS

108

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Drug metabolism can have profound effects on the pharmacological and toxicological profile of therapeutic agents. In the pharmaceutical industry, many in vitro techniques are in place or under development to screen and optimize compounds for favorable metabolic properties in the drug discovery phase. These in vitro technologies are meant to address important issues such as: (1) is the compound a potent inhibitor of drug metabolising enzymes (DMEs)? (2) does the compound induce the expression of DMEs? (3) how labile is the compound to metabolic degradation? (4) which specific enzyme(s) is responsible for the compound's biotransformation? and (5) to which metabolites is the compound metabolized? Answers to these questions provide a basis for judging whether a compound is likely to have acceptable pharmacokinetic properties in vivo. To address these issues on the increasing number of compounds inundating the drug discovery programs, high throughput assays are essential. A combination of biochemical advances in the understanding of the function and regulation of DMEs (in particular, cytochromes P450, CYPs) and automated analytical technologies are revolutionizing drug metabolism research. Automated LC-MS based metabolic stability, fluorescence, radiometric and LC-MS based CYP inhibition assays are now in routine use. Automatible models for studying CYP induction based on enzyme activity, quantitative RT-PCR and reporter gene systems are being developed. We will review the utility and limitations of these HTS approaches and highlight on-going developments and emerging technologies to answer metabolism questions at the different stages of the drug discovery process.

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In Vitro Metabolism

Cited by 22 publications

References 165 publications

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

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

In silico approaches to predicting drug metabolism, toxicology and beyond

In Vitro High Throughput Screening of Compounds for Favorable Metabolic Properties in Drug Discovery.

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