Avoiding physicochemical artefacts in early ADME–Tox experiments

DeWitte, Robert S.

doi:10.1016/j.drudis.2006.07.012

Cited by 27 publications

(14 citation statements)

References 11 publications

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“…However, the greater unbound inhibitor potency and unbound substrate affinity observed here in the protein-containing system can be explained without dismissing the free drug hypothesis but rather by hypothesizing that there is an artifactually low intracellular inhibitor concentration in the protein-free system because of nonspecific loss of inhibitor from the extracellular environment. Although extracellular inhibitor concentrations were not measured in the current report, others have shown that substantial binding to system components can occur in nonprotein media, such as the adsorption of compounds to plastic plates (DeWitte, 2006;Palmgrén et al, 2006). This phenomenon can also explain why the HMM K i, app values for fluconazole and voriconazole were higher than the corresponding plasma K i, app values before correction by f u, p .…”

Section: Mao Et Almentioning

confidence: 58%

Predictions of Cytochrome P450-Mediated Drug-Drug Interactions Using Cryopreserved Human Hepatocytes: Comparison of Plasma and Protein-Free Media Incubation Conditions

Mao¹,

Mohutsky²,

Harrelson³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Cryopreserved human hepatocytes suspended in human plasma (HHSHP) have previously provided accurate CYP3A drug-drug interaction (DDI) predictions from a single IC 50 that captures both reversible and time-dependent inhibition. The goal of this study was to compare the accuracy of DDI predictions by a protein-free human hepatocyte system combined with the fraction unbound in plasma for inhibitor (

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Section: Mao Et Almentioning

confidence: 58%

Predictions of Cytochrome P450-Mediated Drug-Drug Interactions Using Cryopreserved Human Hepatocytes: Comparison of Plasma and Protein-Free Media Incubation Conditions

Mao¹,

Mohutsky²,

Harrelson³

et al. 2012

Drug Metab Dispos

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“…13,129,185,186) Following primary in vitro pharmacology screening, secondary in vitro pharmacology assay for selectivity, in vitro ADME assays, and in vitro toxicology assays are performed (Fig. 19).…”

Section: ‚ Strategies Of Solubility W Dissolution Assessment In Drugmentioning

confidence: 99%

Solubility and Dissolution Profile Assessment in Drug Discovery

Sugano

Okazaki

Sugimoto

et al. 2007

Drug Metabolism and Pharmacokinetics

180

142

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The purposes of the review are to: a) Provide a comprehensible introduction of the-state-of-the-art sciences of solubility and dissolution, b) introduce typical technologies to assess solubility and dissolution, and c) propose the best practice strategy. The theories of solubility and dissolution required in drug discovery were reviewed especially from the view point of oral absorption. The physiological conditions in the gastrointestinal fluid in humans and animals were then briefly summarized. Technologies to assess solubility and dissolution in drug discovery were then introduced. Recently, these technologies have been improved by the laboratory automation and computational technologies. Finally, the strategies to apply these technologies for a drug discovery project were discussed.

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“…It cannot be stressed enough the importance of understanding the confounding effects of DMSO co-solvency artefacts on physicochemical parameters [36][37][38]. Studies have demonstrated the preferential solvation in the aqueous phase due to localised increases in DMSO concentration not apparent in the octan-1-ol phase [39].…”

Section: Lipophilicitymentioning

confidence: 99%

Interpreting physicochemical experimental data sets

Colclough

Wenlock

2015

J Comput Aided Mol Des

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With the wealth of experimental physicochemical data available to chemoinformaticians from the literature, commercial, and company databases an increasing challenge is the interpretation of such datasets. Subtle differences in experimental methodology used to generate these datasets can give rise to variations in physicochemical property values. Such methodology nuances will be apparent to an expert experimentalist but not necessarily to the data analyst and modeller. This paper describes the differences between common methodologies for measuring the four most important physicochemical properties namely aqueous solubility, octan-1-ol/water distribution coefficient, pK(a) and plasma protein binding highlighting key factors that can lead to systematic differences. Insight is given into how to identify datasets suitable for combining.

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Avoiding physicochemical artefacts in early ADME–Tox experiments

Cited by 27 publications

References 11 publications

Predictions of Cytochrome P450-Mediated Drug-Drug Interactions Using Cryopreserved Human Hepatocytes: Comparison of Plasma and Protein-Free Media Incubation Conditions

Predictions of Cytochrome P450-Mediated Drug-Drug Interactions Using Cryopreserved Human Hepatocytes: Comparison of Plasma and Protein-Free Media Incubation Conditions

Solubility and Dissolution Profile Assessment in Drug Discovery

Interpreting physicochemical experimental data sets

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