Drug Interaction Studies Reveal That Simotinib Upregulates Intestinal Absorption by Increasing the Paracellular Permeability of Intestinal Epithelial Cells

Zhu, Qubo; Liu, Zhifang; Li, Pei; Cheng, Zhixiang

doi:10.2133/dmpk.dmpk-13-rg-123

Cited by 11 publications

(6 citation statements)

References 30 publications

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“…Consistent with our conclusions, others have reported that dacomitinib or lapatinib were not directly cytotoxic to T84 cells or in a rat model, respectively (Bowen et al, 2012(Bowen et al, , 2014Van Sebille et al, 2017). Simotinib has also been reported to increase the paracellular permeability of CaCo-2 cells, another human colonic epithelial cell line (Zhu, Liu, Li, & Cheng, 2014).…”

Section: Discussionsupporting

confidence: 92%

Potentiation of calcium‐activated chloride secretion and barrier dysfunction may underlie EGF receptor tyrosine kinase inhibitor‐induced diarrhea

et al. 2020

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFr TKIs) are first‐line therapies for various cancers, and cause dose‐limiting severe diarrhea in many patients. We hypothesized that diarrhea caused by EGFr TKIs might reflect actions on epithelial transport, barrier function, or both, which we tested using cell cultures including murine and human enteroid‐derived monolayers (EDMs), analyzed using electrophysiological and other relevant methods. EGFr TKIs (such as afatinib, erlotinib, and osimertinib) reversed the acute inhibitory effect of EGF on chloride secretion induced by carbachol (CCh) across T84 human colonic epithelial cells, which correlated with the diarrhea‐inducing effect of each agent clinically. EGFr TKIs also reduced transepithelial electrical resistance (TEER), whereas co‐treatment with CCh delayed the decrease in TEER compared with that of cells co‐treated with EGF. Furthermore, afatinib and erlotinib prevented EGF‐ or CCh‐induced EGFr phosphorylation. EGFr TKIs also suppressed phosphorylation of extracellular signal‐regulated kinase (Erk)1/2 in response to EGF, whereas they had weaker effects on CCh‐induced Erk1/2 phosphorylation. In human EDMs, EGF potentiated ion transport induced by CCh, whereas afatinib reversed this effect. The ability of EGFr TKIs to reverse the effects of EGF on calcium‐dependent chloride secretion could contribute to the diarrheal side effects of these agents, and their disruption of epithelial barrier dysfunction is likely also pathophysiologically significant. CCh‐activated Erk1/2 phosphorylation was relatively insensitive to EGFr TKIs and delayed the deleterious effects of EGFr TKIs on barrier function. These findings confirm and extend those of other authors, and may be relevant to designing strategies to overcome the diarrheal side effects of EGFr TKIs.

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Section: Discussionsupporting

confidence: 92%

Potentiation of calcium‐activated chloride secretion and barrier dysfunction may underlie EGF receptor tyrosine kinase inhibitor‐induced diarrhea

et al. 2020

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“…Zhu et al investigated the drug-drug interactions of simotinib [151]. The study revealed the ability of simotinib to increase the paracellular permeability of intestinal epithelial cells, which leads to an upregulation of the intestinal absorption.…”

Section: Biological Activitymentioning

confidence: 99%

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

et al. 2021

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Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.

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“…Da Silva et al, 2015) and on the enhancement of paracellular absorption of hydrophilic drugs (e.g. Dittmann et al, 2014;Zhu et al, 2014).…”

Section: Paracellular Absorption: Beyond Glucose Transportmentioning

confidence: 99%

Integrative physiology of transcellular and paracellular intestinal absorption

Karasov

2017

Journal of Experimental Biology

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Glucose absorption by the small intestine has been studied for nearly a century. Despite extensive knowledge about the identity, functioning and regulation of the relevant transporters, there has been and there remains controversy about how these transporters work in concert to determine the overall epithelial absorption of key nutrients (e.g. sugars, amino acids) over a wide range of dietary and/ or luminal concentrations. Our broader, integrative understanding of intestinal absorption requires more than the reductionist dissection of all the components and their elaboration at molecular and genetic levels. This Commentary emphasizes the integration of discrete molecular players and processes (including paracellular absorption) that, in combination, determine the overall epithelial absorption of key nutrients (e.g. sugars, amino acids) and putative anti-nutrients (watersoluble toxins), and the integration of that absorption with other downstream processes related to metabolic demands. It identifies historic key advances, controversies and future research ideas, as well as important perspectives that arise through comparative as well as biomedical physiological research.

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Drug Interaction Studies Reveal That Simotinib Upregulates Intestinal Absorption by Increasing the Paracellular Permeability of Intestinal Epithelial Cells

Cited by 11 publications

References 30 publications

Potentiation of calcium‐activated chloride secretion and barrier dysfunction may underlie EGF receptor tyrosine kinase inhibitor‐induced diarrhea

Potentiation of calcium‐activated chloride secretion and barrier dysfunction may underlie EGF receptor tyrosine kinase inhibitor‐induced diarrhea

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

Integrative physiology of transcellular and paracellular intestinal absorption

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