Adme

Dowty, Martin E.; Messing, Dean; Lai, Yurong; Kirkovsky, Leonid

doi:10.1002/9780470915110.ch4

Cited by 11 publications

(10 citation statements)

References 160 publications

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“…As already reviewed [23] and suggested by the FDA, PK/PD assessment is one of the main focuses for optimization in the drug development process. This is apparently an idea that was shared among many: whereas ADME evaluation was previously addressed in the late stages of preclinical development, currently it became a major concern throughout the whole DDD process, starting from the very beginnings in drug discovery approaches until the very last steps in lead optimization [21,24].…”

Section: How Specific Parameters Shape the Pharmacology Studiesmentioning

confidence: 99%

“…Passive transport across membranes is defined as permeability, which is dependent on lipophilicity, since biological membranes are virtually lipid bilayers, and is by far the most important transport for small molecules, especially in oral absorption [8,24,29]. Nonlipophilic compounds normally do not traverse membranes passively, while highly lipophilic molecules run the risk to get stuck within the membranes [30].…”

Section: In Vitromentioning

confidence: 99%

“…When dealing with oral administration, it is important to note that the drug is not only confronted with the hurdles of solubility and permeability in the absorption process but is also facing metabolizing mechanisms (i.e., enzymes) in the gastrointestinal tract, which are referred to as first-pass metabolism [24,76]. These include but are not limited to P-glycoproteins, uridine diphosphate glucuronosyltransferase, and mainly cytochrome P450s (CYP450) [24]. This will be discussed more deeply in the Metabolism section.…”

Section: Permeability and The Use Of Cellular And Noncellular Modelsmentioning

confidence: 99%

See 2 more Smart Citations

ADME Profiling in Drug Discovery and a New Path Paved on Silica

Krüger¹,

Wrenger²,

Kronenberger³

2020

Drug Discovery and Development - New Advances

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The drug discovery and development pipeline have more and more relied on in vitro testing and in silico predictions to reduce investments and optimize lead compounds. A comprehensive set of in vitro assays is available to determine key parameters of absorption, distribution, metabolism, and excretion, for example, lipophilicity, solubility, and plasma stability. Such test systems aid the evaluation of the pharmacological properties of a compound and serve as surrogates before entering in vivo testing and clinical trials. Nowadays, computer-aided techniques are employed not just in the discovery of new lead compounds but embedded as part of the entire drug development process where the ADME profiling and big data analyses add a new layer of complexity to those systems. Herein, we give a short overview of the history of the drug development pipeline presenting state-of-theart ADME in vitro assays as established in academia and industry. We will further introduce the underlying good practices and give an example of the compound development pipeline. In the next step, recent advances at in silico techniques will be highlighted with special emphasis on how pharmacogenomics and in silico PK profiling can enhance drug monitoring and individualization of drug therapy.

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Section: How Specific Parameters Shape the Pharmacology Studiesmentioning

confidence: 99%

Section: In Vitromentioning

confidence: 99%

Section: Permeability and The Use Of Cellular And Noncellular Modelsmentioning

confidence: 99%

See 1 more Smart Citation

ADME Profiling in Drug Discovery and a New Path Paved on Silica

Krüger¹,

Wrenger²,

Kronenberger³

2020

Drug Discovery and Development - New Advances

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show abstract

“…The oral administration is the most convenient, safest and least expensive way to deliver a drug; it is the route most often used 31 . During the 1990s almost 40% of the failure in clinical trials was attributed to poor absorption and pharmacokinetics.…”

Section: Other Relevant Propertiesmentioning

confidence: 99%

“…The analysis of 2a, 2e and 2f derivatives (excluding the 2b derivative) demonstrated that there is a relationship between the bound fraction of PP and their lipophilicity (r 2 : 0993), but it is well-known that lipophilicity is one, but not usually the only descriptor that can influence the PP binding 31,41 .…”

Section: Binding Proteinmentioning

confidence: 99%

Synthesis and pharmaceutical properties of N-acyloxymethyl prodrugs of Allop with potential anti-trypanosomal activity

Gualdesi

Ortiz

Raviolo

2015

Drug Development and Industrial Pharmacy

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We report herein the synthesis, and the physicochemical and pharmacokinetic properties of N-acyloxymethyl prodrugs of allopurinol (Allop) (2a-f). Allop is a compound with activity against Trypanosoma cruzi, a causative agent of Chagas disease. Its pathology leads to a huge number of infections and deaths per year, because in addition to many sufferers only having limited access to health services only an inefficient chemotherapy is available. Relevant pharmaceutical properties (pKa, stability, solubility, lipophilicity, in vitro permeability, binding protein, xanthine oxidase binding) were also determined. The results obtained showed that derivatives behave as prodrugs of Allop, since they exhibit improved physicochemical and pharmacokinetic properties relative to their precursor. This behavior turns these compounds into active reservoirs of Allop, and reduces its unfavorable characteristics, so 2a-f compounds are excellent candidates for the treatment of Chagas disease. This work is therefore an important contribution leading to the suppression of Chagas disease.

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Enzymatically Activated Phosphate and Phosphonate Prodrugs

Krylov

McKenna

2013

Enzyme Technologies

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Adme

Cited by 11 publications

References 160 publications

ADME Profiling in Drug Discovery and a New Path Paved on Silica

ADME Profiling in Drug Discovery and a New Path Paved on Silica

Synthesis and pharmaceutical properties of N-acyloxymethyl prodrugs of Allop with potential anti-trypanosomal activity

Enzymatically Activated Phosphate and Phosphonate Prodrugs

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