Passive Permeability and Active Transport Models for the Prediction of Oral Absorption

Artursson, Per; Tavelin, Staffan; Matsson, Pär

doi:10.1016/b0-08-045044-x/00126-7

Cited by 13 publications

(9 citation statements)

References 209 publications

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“…HPLC-MS/MS analysis was performed by the Sapiotec GmbH in Würzburg. The apparent permeability coefficient (P app ) was calculated according to Artursson et al 9 , 25 …”

Section: Methodsmentioning

confidence: 99%

Enhancing pre-clinical research with simplified intestinal cell line models

Fey,

Truschel,

Nehlsen

et al. 2024

J Tissue Eng

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Two-dimensional culture remains widely employed to determine the bioavailability of orally delivered drugs. To gain more knowledge about drug uptake mechanisms and risk assessment for the patient after oral drug admission, intestinal in vitro models demonstrating a closer similarity to the in vivo situation are needed. In particular, Caco-2 cell-based Transwell® models show advantages as they are reproducible, cost-efficient, and standardized. However, cellular complexity is impaired and cell function is strongly modified as important transporters in the apical membrane are missing. To overcome these limitations, primary organoid-based human small intestinal tissue models were developed recently but the application of these cultures in pre-clinical research still represents an enormous challenge, as culture setup is complex as well as time- and cost-intensive. To overcome these hurdles, we demonstrate the establishment of primary organoid-derived intestinal cell lines by immortalization. Besides exhibiting cellular diversity of the organoid, these immortalized cell lines enable a standardized and more cost-efficient culture. Further, our cell line-based Transwell®-like models display an organ-specific epithelial barrier integrity, ultrastructural features and representative transport functions. Altogether, our novel model systems are cost-efficient with close similarity to the in vivo situation, therefore favoring their use in bioavailability studies in the context of pre-clinical screenings.

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“…HPLC-MS/MS analysis was performed by the Sapiotec GmbH in Würzburg. The apparent permeability coefficient (P app ) was calculated according to Artursson et al 9 , 25 …”

Section: Methodsmentioning

confidence: 99%

Enhancing pre-clinical research with simplified intestinal cell line models

Fey,

Truschel,

Nehlsen

et al. 2024

J Tissue Eng

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show abstract

“…Due to the overall importance of maintaining good permeability in most traditional programs, many teams will want an early understanding of the likelihood of permeability problems with the series of interest. Typical early in vitro permeability assessments measure the rate of flux of a compound from one side of a barrier to another [54,55]. The barrier has historically been derived from a cell line, most commonly Caco-2 or Madin-Darby canine kidney (MDCK) cells.…”

Section: Permeability/absorptionmentioning

confidence: 99%

Hit Triage: Medicinal Chemistry Strategies to Improve the Odds of Success in Discovery

Freeman‐Cook

Kung²

2009

Topics in Medicinal Chemistry

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This chapter describes the process of collecting and analyzing information in order to make decisions which help a project move through a key early stage in drug discovery. It explains, in general, the sources of hits for a drug discovery program and explores the link between potency and efficiency in evaluating lead matter. The chapter then illustrates the collection of both pharmacokinetic data as well as safety data, and describes the relevance of that data and the process of using it to make decisions. Of course, there is no one ''right'' or ''wrong'' way to do the work contained in this chapter, but the practice of efficiently building a network of information on compounds, and then using that to make informed decisions can help to shift the odds of success in drug discovery.

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“…Absorption of oral drugs is a complex business and involves multiple mechanisms across the GI mucosa [76] . A number of in vitro models were developed to predict permeability as well as to assess the contributions of active transporters in the permeation process [77,78] .…”

Section: In Vitro Models For Permeability and Active Transportersmentioning

confidence: 99%

Maximising use ofin vitroADMET tools to predictin vivobioavailability and safety

Wang¹,

Urbán²,

Bojanic³

2007

Expert Opinion on Drug Metabolism & Toxicology

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The drastic increase in the costs for discovering and developing a new drug and the high attrition rate of development candidates led to shifting of drug discovery strategy to parallel assessment of comprehensive drug properties along with efficacy. The article reviews the benefits and caveats of implementing comprehensive in vitro tools in early drug discovery and their impact on addressing in vivo ADMET issues. With the proposal of four-barrier profiling paradigm and employment of integrated risk assessment, one can exponentially enhance the predictive power of those in vitro tools by taking into consideration the interplays among those profiling parameters. An 'Exposure Cube' is proposed to promote collective employment of solubility/dissolution, permeability and metabolic clearance to address in vivo exposure and to direct optimization of new chemical entities in drug discovery.

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Passive Permeability and Active Transport Models for the Prediction of Oral Absorption

Cited by 13 publications

References 209 publications

Enhancing pre-clinical research with simplified intestinal cell line models

Enhancing pre-clinical research with simplified intestinal cell line models

Hit Triage: Medicinal Chemistry Strategies to Improve the Odds of Success in Discovery

Maximising use ofin vitroADMET tools to predictin vivobioavailability and safety

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