High Throughput ADME Screening: Practical Considerations, Impact on the Portfolio and Enabler of In Silico ADME Models

Hop, Cornelis E. C. A.; Cole, Mark J.; Davidson, Ralph E.; Duignan, David B.; Federico, James J.; Janiszewski, John; Jenkins, Kelly M.; Krueger, Suzanne S.; Lebowitz, Rebecca Blazar; Liston, Theodore E.; Mitchell, Walter; Snyder, Mark A.; Steyn, Stefan J.; Soglia, John R.; Taylor, Christine; Troutman, Matt; Umland, John P.; West, Michael; Whalen, Kevin M.; Zelesky, Veronica; Zhao, Sabrina X.

doi:10.2174/138920008786485092

Cited by 82 publications

(45 citation statements)

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“…The ADME assays were performed via reported methods as described previously for MDCK P app (14), MDR-MDCK P-gp (14), and metabolic stability (14,15,22,35).…”

Section: Data Collectionmentioning

confidence: 99%

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

Wager

Chandrasekaran

Hou

et al. 2010

ACS Chem. Neurosci.

402

401

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As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.

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“…The ADME assays were performed via reported methods as described previously for MDCK P app (14), MDR-MDCK P-gp (14), and metabolic stability (14,15,22,35).…”

Section: Data Collectionmentioning

confidence: 99%

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

Wager

Chandrasekaran

Hou

et al. 2010

ACS Chem. Neurosci.

402

401

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“…Low-clearance compounds in drug discovery are increasingly more prevalent for a number of reasons. First, high-throughput metabolic stability assays in conjunction with metabolite identification enable rapid development of structure-metabolic stability relationships (Di and Kerns, 2003;Di et al, 2008;Hop et al, 2008). Effective design strategies have been put into place to overcome metabolic liabilities through structural modifications Di et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

A Novel Relay Method for Determining Low-Clearance Values

et al. 2012

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ABSTRACT:A novel relay method has been developed using cryopreserved human hepatocytes to measure intrinsic clearance of low-clearance compounds. The relay method involved transferring the supernatant from hepatocyte incubations to freshly thawed hepatocytes at the end of the 4-h incubation to prolong the exposure time to active enzymes in hepatocytes. An accumulative incubation time of 20 h or longer in hepatoctyes can be achieved using the method. The relay method was validated using seven commercial drugs (diazepam, disopyramide, theophylline, timolol, tolbutamide, S-warfarin, and zolmitriptan) that were metabolized by various cytochrome P450s with low human in vivo intrinsic clearance at approximately 2 to 15 ml ⅐ min ؊1 ⅐ kg ؊1. The results showed that the relay method produced excellent predictions of human in vivo clearance. The difference between in vitro and in vivo intrinsic clearance was within 2-fold for most compounds, which is similar to the standard prediction accuracy for moderate to high clearance compounds using hepatocytes. The relay method is a straightforward, relatively low cost, and easy-to-use new tool to address the challenges of low clearance in drug discovery and development.

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“…Toward this effort, implementation of in vitro DMPK screening assays (e.g., metabolic stability) early in discovery phase programs became the paradigm, which has had significant positive impact on pharmacokinetic properties, resulting in marked improvement in later-stage drug candidate attrition (Kola and Landis, 2004). Due to these successes, modern drug discovery programs have generally adopted a parallel optimization strategy for absorption, distribution, metabolism, and excretion (ADME) properties along with pharmacological target potency in an effort to expedite the process of discovering suitable drug candidates for clinical investigations (Di et al, 2008;Hop et al, 2008). Because of these advances, selection of a drug candidate with a reasonably low-dose and dose-frequency projection is the expectation to enable decision making around investment in expensive clinical programs.…”

Section: Introductionmentioning

confidence: 99%

Low-Turnover Drug Molecules: A Current Challenge for Drug Metabolism Scientists

2015

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In vitro assays using liver subcellular fractions or suspended hepatocytes for characterizing the metabolism of drug candidates play an integral role in the optimization strategy employed by medicinal chemists. However, conventional in vitro assays have limitations in their ability to predict clearance and generate metabolites for lowturnover (slowly metabolized) drug molecules. Due to a rapid loss in the activity of the drug-metabolizing enzymes, in vitro incubations are typically performed for a maximum of 1 hour with liver microsomes to 4 hours with suspended hepatocytes. Such incubations are insufficient to generate a robust metabolic response for compounds that are slowly metabolized. Thus, the challenge of accurately estimating low human clearance with confidence has emerged to be among the top challenges that drug metabolism scientists are confronted with today. In response, investigators have evaluated novel methodologies to extend incubation times and more sufficiently measure metabolism of low-turnover drugs. These methods include plated human hepatocytes in monoculture, and a novel in vitro methodology using a relay of sequential incubations with suspended cryopreserved hepatocytes. In addition, more complex in vitro cellular models, such as HepatoPac (Hepregen, Medford, MA), a micropatterned hepatocyte-fibroblast coculture system, and the HmREL (Beverley Hills, CA) hepatic coculture system, have been developed and characterized that demonstrate prolonged enzyme activity. In this review, the advantages and disadvantages of each of these in vitro methodologies as it relates to the prediction of clearance and metabolite identification will be described in an effort to provide drug metabolism scientists with the most up-to-date experimental options for dealing with the complex issue of low-turnover drug candidates.

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High Throughput ADME Screening: Practical Considerations, Impact on the Portfolio and Enabler of In Silico ADME Models

Cited by 82 publications

References 0 publications

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

A Novel Relay Method for Determining Low-Clearance Values

Low-Turnover Drug Molecules: A Current Challenge for Drug Metabolism Scientists

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