Biopharmaceutics Classification of Selected β-Blockers:  Solubility and Permeability Class Membership

Yang, Yongsheng; Faustino, Patrick J.; Volpe, Donna A.; Ellison, Christopher D.; Lyon, Robbe C.; Yu, Lawrence X.

doi:10.1021/mp070028i

Cited by 92 publications

(95 citation statements)

References 28 publications

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“…In addition, nadolol, a low passive permeability benchmark, was also used to confirm the integrity of the monolayers of Caco-2 cells. The permeability values of nadolol were within the acceptable range of the in-house data (on file at Incyte Corporation) and were also consistent with the values reported in the literature (Yang et al, 2007). All transport experiments were conducted between 22 and 25 days after seeding.…”

Section: [ 3 H]thiamine and [supporting

confidence: 83%

The Janus Kinase 2 Inhibitor Fedratinib Inhibits Thiamine Uptake: A Putative Mechanism for the Onset of Wernicke’s Encephalopathy

Zhang

Diamond

et al. 2014

Drug Metab Dispos

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The clinical development of fedratinib, a Janus kinase (JAK2) inhibitor, was terminated after reports of Wernicke's encephalopathy in myelofibrosis patients. Since Wernicke's encephalopathy is induced by thiamine deficiency, investigations were conducted to probe possible mechanisms through which fedratinib may lead to a thiamine-deficient state. In vitro studies indicate that fedratinib potently inhibits the carrier-mediated uptake and transcellular flux of thiamine in Caco-2 cells, suggesting that oral absorption of dietary thiamine is significantly compromised by fedratinib dosing. Transport studies with recombinant human thiamine transporters identified the individual human thiamine transporter (hTHTR2) that is inhibited by fedratinib. Inhibition of thiamine uptake appears unique to fedratinib and is not shared by marketed JAK inhibitors, and this observation is consistent with the known structure-activity relationship for the binding of thiamine to its transporters. The results from these studies provide a molecular basis for the development of Wernicke's encephalopathy upon fedratinib treatment and highlight the need to evaluate interactions of investigational drugs with nutrient transporters in addition to classic xenobiotic transporters.

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Section: [ 3 H]thiamine and [supporting

confidence: 83%

The Janus Kinase 2 Inhibitor Fedratinib Inhibits Thiamine Uptake: A Putative Mechanism for the Onset of Wernicke’s Encephalopathy

Zhang

Diamond

et al. 2014

Drug Metab Dispos

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“…Pregabalin is an example of a hydrophilic compound whose high extent of absorption was long believed to result from paracellular diffusion until a highly expressed amino acid transporter was implicated in its intestinal transport (53). Similarly, we believe that the high extent of absorption and low Caco-2 permeability of sotalol likely involves a highly expressed intestinal transporter in contrast to some authors who hypothesize that sotalol's high extent of absorption is due to paracellular diffusion (12,41,74). For these Case 3 drugs, Caco-2 will not be able to predict the high intestinal absorption of these hydrophilic compounds due to the cellular membrane's significant underexpression of relevant transporters compared to the human intestine.…”

Section: Differences In the Paracellular Junctions Between Caco-2 Andmentioning

confidence: 70%

“…Yee (10) had reported that Caco-2 can accurately predict the human intestinal permeability or absorption of compounds regardless of transcellular, paracellular, and carrier-mediated transport mechanisms. However, there are Caco-2 permeability results that disagree with measured human intestinal permeability rates or measured extents of human intestinal absorption (11,12).…”

Section: Introductionmentioning

confidence: 91%

Drug Discovery and Regulatory Considerations for Improving In Silico and In Vitro Predictions that Use Caco-2 as a Surrogate for Human Intestinal Permeability Measurements

Larregieu

Benet

2013

AAPS J

131

119

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ABSTRACT. There is a growing need for highly accurate in silico and in vitro predictive models to facilitate drug discovery and development. Results from in vitro permeation studies across the Caco-2 cell monolayer are commonly used for drug permeability screening in industry and are also accepted as a surrogate for human intestinal permeability measurements by the US FDA to support new drug applications. Countless studies carried out in this cell line with published permeability measurements have enabled the development of many in silico prediction models. We identify several common cases that illustrate how using Caco-2 permeability measurements in these in silico and in vitro predictive models will not correlate with human intestinal permeability and will further lead to inaccuracies in these models. We provide guidelines and recommendations for improving these models to more accurately predict clinically relevant information, thereby enhancing the drug discovery, development, and regulatory approval processes.

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“…9,10) These differences are considered to be attributed to the presence of an unstirred water layer (UWL) on the surface of epithelial cells. [11][12][13] A UWL is a considerable permeability barrier that greatly affects in vitro, but not in vivo, drug absorption experiments.…”

mentioning

confidence: 99%

Effect of Mechanical Agitation on Cationic Liposome Transport across an Unstirred Water Layer in Caco-2 Cells

Kono

Iwasaki

Matsuoka

et al. 2016

Biological & Pharmaceutical Bulletin

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To develop an effective oral delivery system for plasmid DNA (pDNA) using cationic liposomes, it is necessary to clarify the characteristics of uptake and transport of cationic liposome/pDNA complexes into the intestinal epithelium. In particular, evaluation of the involvement of an unstirred water layer (UWL), which is a considerable permeability barrier, in cationic liposome transport is very important. Here, we investigated the effects of a UWL on the transfection efficiency of cationic liposome/pDNA complexes into a Caco-2 cell monolayer. When Caco-2 cells were transfected with cationic liposome/pDNA complexes in shaking cultures to reduce the thickness of the UWL, gene expression was significantly higher in Caco-2 cells compared with static cultures. We also found that this enhancement of gene expression by shaking was not attributable to activation of transcription factors such as activator protein-1 and nuclear factor-kappaB (NF-κB). In addition, the increase in gene expression by mechanical agitation was observed at all charge ratios (1.5, 2.3, 3.1, 4.5) of cationic liposome/pDNA complexes. Transport experiments using Transwells demonstrated that mechanical agitation increased the uptake of cationic liposome/pDNA complexes by Caco-2 cells, whereas transport of the complexes across a Caco-2 cell monolayer did not occurr. Moreover, the augmentation of the gene expression of cationic liposome/pDNA complexes by shaking was observed in Madin-Darby canine kidney cells. These results indicate that a UWL greatly affects the uptake and transfection efficiency of cationic liposome/pDNA complexes into an epithelial monolayer in vitro.

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Biopharmaceutics Classification of Selected β-Blockers: Solubility and Permeability Class Membership

Cited by 92 publications

References 28 publications

The Janus Kinase 2 Inhibitor Fedratinib Inhibits Thiamine Uptake: A Putative Mechanism for the Onset of Wernicke’s Encephalopathy

The Janus Kinase 2 Inhibitor Fedratinib Inhibits Thiamine Uptake: A Putative Mechanism for the Onset of Wernicke’s Encephalopathy

Drug Discovery and Regulatory Considerations for Improving In Silico and In Vitro Predictions that Use Caco-2 as a Surrogate for Human Intestinal Permeability Measurements

Effect of Mechanical Agitation on Cationic Liposome Transport across an Unstirred Water Layer in Caco-2 Cells

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