Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

Kaddurah‐Daouk, Rima; Hankemeier, Thomas; Scholl, Elizabeth H.; Baillie, Rebecca; Harms, Amy C.; Stage, Claus; Dalhoff, Kim; Jürgens, Gesche; Taboureau, Olivier; Nzabonimpa, Grace Shema; Motsinger‐Reif, Alison A.; Thomsen, Ragnar; Línnet, Kristían; Rasmussen, Henrik Berg

doi:10.1002/psp4.12309

Cited by 15 publications

(6 citation statements)

References 39 publications

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“…CES1 is involved in drug detoxification and metabolism of endogenous metabolites, including cholesterol and triglycerides ( Redinbo et al., 2003 ). Interestingly, docking studies revealed that BAs can bind the catalytic site of CES1, with CDCA and TCA having the strongest binding activity ( Kaddurah-Daouk et al., 2018 ). Further mechanistic studies will be required to gain further insight into this CES1-BA interaction.…”

Section: Discussionmentioning

confidence: 99%

Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis

Perino

Huang

et al. 2022

Cell Metabolism

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Section: Discussionmentioning

confidence: 99%

Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis

Perino

Huang

et al. 2022

Cell Metabolism

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“…CES1 mRNA expression level in adipose tissue was positively associated with body mass index (P , 0.001), fasting glucose level (P 5 0.002), insulin (P 5 0.006), and triglycerides (P 5 0.003) (Friedrichsen et al, 2013). Recent studies have also found that CES1 function was positively correlated with increased liver lipid storage and plasma lipid concentrations, indicating that CES1 might be heavily involved in lipid metabolism and is a potential drug target for the treatment of human metabolic disorders (Kaddurah-Daouk et al, 2018;Lian et al, 2018a,b).…”

Section: Disease States Related To Ces1mentioning

confidence: 98%

Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators

Her

Zhu

2019

Drug Metab Dispos

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Carboxylesterase (CES) 1 is the most abundant drug-metabolizing enzyme in human livers, comprising approximately 1% of the entire liver proteome. CES1 is responsible for 80%-95% of total hydrolytic activity in the liver and plays a crucial role in the metabolism of a wide range of drugs (especially ester-prodrugs), pesticides, environmental pollutants, and endogenous compounds. Expression and activity of CES1 vary markedly among individuals, which is a major contributing factor to interindividual variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by CES1. Both genetic and nongenetic factors contribute to CES1 variability. Here, we discuss genetic polymorphisms, including singlenucleotide polymorphisms (SNPs), and copy number variants and nongenetic contributors, such as developmental status, genders, and drug-drug interactions, that could influence CES1 functionality and the PK and PD of CES1 substrates. Currently, the loss-of-function SNP G143E (rs71647871) is the only clinically significant CES1 variant identified to date, and alcohol is the only potent CES1 inhibitor that could alter the therapeutic outcomes of CES1 substrate medications. However, G143E and alcohol can only explain a small portion of the interindividual variability in the CES1 function. A better understanding of the regulation of CES1 expression and activity and identification of biomarkers for CES1 function in vivo could lead to the development of a precision pharmacotherapy strategy to improve the efficacy and safety of many CES1 substrate drugs. SIGNIFICANCE STATEMENTThe clinical relevance of CES1 has been well demonstrated in various clinical trials. Genetic and nongenetic regulators can affect CES1 expression and activity, resulting in the alteration of the metabolism and clinical outcome of CES1 substrate drugs, such as methylphenidate and clopidogrel. Predicting the hepatic CES1 function can provide clinical guidance to optimize pharmacotherapy of numerous medications metabolized by CES1.

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“…This nucleophile then attacks the carbonyl carbon of the ester substrate, leading to the formation of the acyl-enzyme intermediate, which is stabilized by the oxyanion hole residues Gly142 and Gly143. Additionally, the enzyme has two other ligand-binding sites referred to as the side-door and the Z-site: The side-door serves as an alternative/additional opening to the active site for substrate entrance or as a product release pore: The Z-site probably has an allosteric function by modulation of the binding site accessibility [45,46]. However, the side-door and the Z-site binding sites were not investigated in this study.…”

Section: Resultsmentioning

confidence: 99%

Combined Ensemble Docking and Machine Learning in Identification of Therapeutic Agents with Potential Inhibitory Effect on Human CES1

et al. 2019

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The human carboxylesterase 1 (CES1), responsible for the biotransformation of many diverse therapeutic agents, may contribute to the occurrence of adverse drug reactions and therapeutic failure through drug interactions. The present study is designed to address the issue of potential drug interactions resulting from the inhibition of CES1. Based on an ensemble of 10 crystal structures complexed with different ligands and a set of 294 known CES1 ligands, we used docking (Autodock Vina) and machine learning methodologies (LDA, QDA and multilayer perceptron), considering the different energy terms from the scoring function to assess the best combination to enable the identification of CES1 inhibitors. The protocol was then applied on a library of 1114 FDA-approved drugs and eight drugs were selected for in vitro CES1 inhibition. An inhibition effect was observed for diltiazem (IC50 = 13.9 µM). Three others drugs (benztropine, iloprost and treprostinil), exhibited a weak CES1 inhibitory effects with IC50 values of 298.2 µM, 366.8 µM and 391.6 µM respectively. In conclusion, the binding site of CES1 is relatively flexible and can adapt its conformation to different types of ligands. Combining ensemble docking and machine learning approaches improves the prediction of CES1 inhibitors compared to a docking study using only one crystal structure.

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Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

Cited by 15 publications

References 39 publications

Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis

Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis

Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators

Combined Ensemble Docking and Machine Learning in Identification of Therapeutic Agents with Potential Inhibitory Effect on Human CES1

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