Downregulated expression of intestinal P-glycoprotein in rats with cisplatin-induced acute kidney injury causes amplification of its transport capacity to maintain “gatekeeper” function

Takeda, Fuyo; Oda, Masayuki; Terasaki, Masaru; Ichimura, Yuichi; Kojima, Hiroyuki; Shinmoto, Hiroshi

doi:10.1016/j.taap.2021.115570

Cited by 6 publications

(3 citation statements)

References 33 publications

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“…Therefore, the researchers concluded that P-gp could maintain its role by increasing its activity. However, no changes were observed in the BCRP expression in the cisplatininduced acute kidney injury rats [127].…”

Section: In Vivo Modelsmentioning

confidence: 82%

Study Models of Drug–Drug Interactions Involving P-Glycoprotein: The Potential Benefit of P-Glycoprotein Modulation at the Kidney and Intestinal Levels

Veiga-Matos,

Morales,

Prieto

et al. 2023

Molecules

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P-glycoprotein (P-gp) is a crucial membrane transporter situated on the cell’s apical surface, being responsible for eliminating xenobiotics and endobiotics. P-gp modulators are compounds that can directly or indirectly affect this protein, leading to changes in its expression and function. These modulators can act as inhibitors, inducers, or activators, potentially causing drug–drug interactions (DDIs). This comprehensive review explores diverse models and techniques used to assess drug-induced P-gp modulation. We cover several approaches, including in silico, in vitro, ex vivo, and in vivo methods, with their respective strengths and limitations. Additionally, we explore the therapeutic implications of DDIs involving P-gp, with a special focus on the renal and intestinal elimination of P-gp substrates. This involves enhancing the removal of toxic substances from proximal tubular epithelial cells into the urine or increasing the transport of compounds from enterocytes into the intestinal lumen, thereby facilitating their excretion in the feces. A better understanding of these interactions, and of the distinct techniques applied for their study, will be of utmost importance for optimizing drug therapy, consequently minimizing drug-induced adverse and toxic effects.

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Section: In Vivo Modelsmentioning

confidence: 82%

Study Models of Drug–Drug Interactions Involving P-Glycoprotein: The Potential Benefit of P-Glycoprotein Modulation at the Kidney and Intestinal Levels

Veiga-Matos,

Morales,

Prieto

et al. 2023

Molecules

View full text Add to dashboard Cite

show abstract

“…This will lead to the up-regulation of MRP and the down-regulation of OCT2, while, for hyperuricemia rats, in acute kidney injury, P-gp, MRP2 and other transporters will be significantly upregulated [ 15 , 16 ]. These changes may be due to the activation or induction of some upstream nuclear receptors under pathological conditions, such as PPAR-α and other nuclear receptors and transcription factors, thereby regulating the expression of downstream transporters [ 17 , 18 ], LXR and FXR are associated with Abcg1 gene and Abc -related protein expression, and its expression can cause changes in downstream transporters. PXR is associated with Slc -related protein expression and Abc -related protein expression, just like Mdr-1α and Slc16a1 [ 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics

et al. 2022

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With the widespread clinical use of drug combinations, the incidence of drug–drug interactions (DDI) has significantly increased, accompanied by a variety of adverse reactions. Drug transporters play an important role in the development of DDI by affecting the elimination process of drugs in vivo, especially in the pathological state. Tubulointerstitial fibrosis (TIF) is an inevitable pathway in the progression of chronic kidney disease (CKD) to end-stage renal disease. Here, the dynamic expression changes of eleven drug transporters in TIF kidney have been systematically investigated. Among them, the mRNA expressions of Oat1, Oat2, Oct1, Oct2, Oatp4C1 and Mate1 were down-regulated, while Oat3, Mrp2, Mrp4, Mdr1-α, Bcrp were up-regulated. Pearson correlation analysis was used to analyze the correlation between transporters and Creatinine (Cr), OCT2 and MATE1 showed a strong negative correlation with Cr. In contrast, Mdr1-α exhibited a strong positive correlation with Cr. In addition, the pharmacokinetics of cimetidine, ganciclovir, and digoxin, which were the classical substrates for OCT2, MATE1 and P-glycoprotein (P-gp), respectively, have been studied. These results reveal that changes in serum creatinine can indicate changes in drug transporters in the kidney, and thus affect the pharmacokinetics of its substrates, providing useful information for clinical use.

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“…Predicting the potential changes in the pharmacokinetic profiles of CP and sunitinib in the presence of CTX is a warranted research avenue. Given the changes in the cellular permeability to these molecules, it is important to evaluate the safety of the combination therapies in the liver and kidneys, organs with a high expression and activity of multiple drug transporters that are also sensitive to both sunitinib [ 19 ] and CP [ 20 ], respectively.…”

Section: Discussionmentioning

confidence: 99%

Recapitulating the Pharmacological Interactions of Cetuximab with Sunitinib and Cisplatin in Head and Neck Carcinoma Cells in vitro

et al. 2022

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Introduction: Cisplatin is extensively used in the treatment of head and neck carcinomas. Cetuximab combination therapy is employed in recurrent and metastatic settings. Sunitinib showed positive results in the treatment of head and neck carcinomas, both as monotherapy or in combination with cetuximab. Nonetheless, the mechanism governing these pharmacological interactions is largely unresolved. This study investigates the impact of cetuximab on the cytotoxicity of cisplatin and sunitinib using cells representative of head and neck carcinoma and the oral epithelium. Methods: The uptake and efflux activities of cells were determined using the prototypical fluorescent substrates 4-[4-[dimethylamino]styryl)-1-methyl pyridinium iodide, Hoechst 33342, and calcein-AM in the presence or absence of specific inhibitors in cells pretreated with cetuximab. The expression of key uptake and efflux drug transporters was analyzed using qPCR and immunofluorescence. Cisplatin and sunitinib cytotoxicities after cetuximab pretreatment were evaluated using the PrestoBlue viability assay. Results: Both tumor and nontumor cells showed significant active drug transport activity. Cetuximab substantially deregulated the expression of key transporters involved in drug resistance in head and neck cancer cells. Transporter expression in the nontumor cell was unaffected. Upon cetuximab pretreatment, the half maximal effective toxic concentration of cisplatin was reduced by 0.75-fold and sunitinib by 0.82-fold in cancer cells. Nontumor cells were not sensitive to cisplatin or sunitinib under the conditions tested. Conclusion: Cetuximab regulates the expression and activity of key membrane drug transporters in head and neck cancer cells, involved in drug resistance. The deregulation of the transport mechanism behind cisplatin and sunitinib uptake reverses drug resistance and enhances the cytotoxicity of both drugs.

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Downregulated expression of intestinal P-glycoprotein in rats with cisplatin-induced acute kidney injury causes amplification of its transport capacity to maintain “gatekeeper” function

Cited by 6 publications

References 33 publications

Study Models of Drug–Drug Interactions Involving P-Glycoprotein: The Potential Benefit of P-Glycoprotein Modulation at the Kidney and Intestinal Levels

Study Models of Drug–Drug Interactions Involving P-Glycoprotein: The Potential Benefit of P-Glycoprotein Modulation at the Kidney and Intestinal Levels

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics

Recapitulating the Pharmacological Interactions of Cetuximab with Sunitinib and Cisplatin in Head and Neck Carcinoma Cells in vitro

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