P-glycoprotein Mediated Efflux Modulators of Plant Origin: A Short Review

Silva, Nuno A.; Salgueiro, Lígia; Fortuna, Ana; Cavaleiro, Carlos

doi:10.1177/1934578x1601100538

Cited by 11 publications

(13 citation statements)

References 38 publications

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“…Therefore, food–drug, plant–drug, and herbal medicine–drug interactions should be considered in these cases. More research is required to investigate these natural products by identifying their optimized inhibitory concentrations, pharmacokinetic properties, potential toxicities, and possible drug–drug interactions [ 116 ].…”

Section: Classification Of P-gp Inhibitorsmentioning

confidence: 99%

“…First, when natural constituents are used as P-gp inhibitors, their pharmacokinetic properties, potential toxicity, and possible drug–drug interactions should be determined because they may have their own pharmacological activity. In addition, the optimal inhibitory concentrations for P-gp inhibition must be defined [ 116 ]. Second, the co-administration or co-delivery of P-gp inhibitor drugs and natural constituents with drug delivery systems containing P-gp substrates may or may not show beneficial effects.…”

Section: Outlooks and Concluding Remarksmentioning

confidence: 99%

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Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability

2021

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P-glycoprotein (P-gp) is crucial in the active transport of various substrates with diverse structures out of cells, resulting in poor intestinal permeation and limited bioavailability following oral administration. P-gp inhibitors, including small molecule drugs, natural constituents, and pharmaceutically inert excipients, have been exploited to overcome P-gp efflux and enhance the oral absorption and bioavailability of many P-gp substrates. The co-administration of small molecule P-gp inhibitors with P-gp substrates can result in drug–drug interactions and increased side effects due to the pharmacological activity of these molecules. On the other hand, pharmaceutically inert excipients, including polymers, surfactants, and lipid-based excipients, are safe, pharmaceutically acceptable, and are not absorbed from the gut. Notably, they can be incorporated in pharmaceutical formulations to enhance drug solubility, absorption, and bioavailability due to the formulation itself and the P-gp inhibitory effects of the excipients. Different formulations with inherent P-gp inhibitory activity have been developed. These include micelles, emulsions, liposomes, solid lipid nanoparticles, polymeric nanoparticles, microspheres, dendrimers, and solid dispersions. They can bypass P-gp by different mechanisms related to their properties. In this review, we briefly introduce P-gp and P-gp inhibitors, and we extensively summarize the current development of oral drug delivery systems that can bypass and inhibit P-gp to improve the oral absorption and bioavailability of P-gp substrates. Since many drugs are limited by P-gp-mediated efflux, this review is helpful for designing suitable formulations of P-gp substrates to enhance their oral absorption and bioavailability.

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Section: Classification Of P-gp Inhibitorsmentioning

confidence: 99%

Section: Outlooks and Concluding Remarksmentioning

confidence: 99%

Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability

2021

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“…P-gp is a transmembrane glycoprotein encoded by MDR gene MDR1 with a molecular weight of ~170 kDa. It exhibits a high expression on multidrug-resistant cell membranes and can pump out anticancer drugs ( 45 ), resulting in the decrease in intracellular drug concentration, reduced drug cytotoxicity, and ultimately drug resistance. In addition, P-gp has recently been shown that it may confer resistance to chemotherapy-induced apoptosis ( 46 ).…”

Section: Micrornas Modulate Drug Resistance-related Mechanisms In Hepmentioning

confidence: 99%

MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma

Liang

Qiao

et al. 2020

Front. Oncol.

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Primary liver cancer [hepatocellular carcinoma (HCC)] is one of the most common malignant tumors worldwide, causing serious health threats because of its high morbidity and mortality, rapid growth, and strong invasiveness. Patients with HCC frequently develop resistance to the current chemotherapeutic drugs, and this is largely attributed to the high-level heterogeneity of the tumor tissue. MicroRNAs (miRNAs) are a group of master regulators for multiple physiological and pathological processes and play important roles in the tumorigenesis. More recent studies have indicated that miRNAs also play a non-negligible role in the development of drug resistance in liver cancer. In this review, we summarize the data from the latest studies on the mechanisms of drug resistance in liver cancer, including autophagy, membrane transporters, epithelial–mesenchymal transitions (EMTs), tumor microenvironment, and genes and proteins that are associated with apoptosis. The data herein will provide valuable information for the development of novel approaches to tackle drug resistance in the management of liver cancer.

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“…To circumvent the above limitations, researchers have shown much interest in phytochemicals as lead molecules for P‐gp inhibition due to the broad chemical diversity and biological potential (Abdallah, Al‐Abd, El‐Dine, & El‐Halawany, 2015; Silva, Salgueiro, Fortuna, & Cavaleiro, 2016; Syed & Coumar, 2016). However, many of them are also reported as inhibitors of CYP enzymes (Syed & Coumar, 2016).…”

Section: Introductionmentioning

confidence: 99%

Overcoming vincristine resistance in cancer: Computational design and discovery of piperine‐inspired P‐glycoprotein inhibitors

et al. 2020

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P-glycoprotein (P-gp)/MDR-1 plays a major role in the development of multidrug resistance (MDR) by pumping the chemotherapeutic drugs out of the cancer cells and reducing their efficacy. A number of P-gp inhibitors were reported to reverse the MDR when co-administered with chemotherapeutic drugs. Unfortunately, none has approved for clinical use due to toxicity issues. Some of the P-gp inhibitors tested in the clinics are reported to have cross-reactivity with CYP450 drug-metabolizing enzymes, resulting in unpredictable pharmacokinetics and toxicity of co-administered chemotherapeutic drugs. In this study, two piperine analogs (3 and 4) having lower cross-reactivity with CYP3A4 drug-metabolizing enzyme are identified as P-glycoprotein (P-gp) inhibitors through computational design, followed by synthesis and testing in MDR cancer cell lines over-expressing P-gp (KB Ch R 8-5, SW480-VCR, and HCT-15). Both the analogs significantly increased the vincristine efficacy in MDR cancer cell lines at low micromole concentrations. Specifically, 3 caused complete reversal of vincristine resistance in KB Ch R 8-5 cells and found to act as competitive inhibitor of P-gp as well as potentiated the vincristine-induced NF-KBmediated apoptosis. Therefore, 3 ((2E,4E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-hydroxy-3-methoxyphenyl)penta-2,4-dien-1-one) can serve as a potential P-gp inhibitor for in vivo investigations, to reverse multidrug resistance in cancer. 52 | SYED Et al. 1 | INTRODUCTION P-glycoprotein (P-gp/MDR-1) belonging to the ABC family of efflux pump transporters plays an important role in the development of drug resistance in cancer (Ghaleb et al., 2018; Waghray & Zhang, 2018). From the clinical studies, it is evident that the expression of MDR-1 is inversely proportional to the efficacy of first-line chemotherapy (Chung, Santiago, De Jesus, Trinidad, & See, 2016). Moreover, some of the clinical studies have also revealed an increased expression of P-gp after chemotherapy, which positively correlates with the relapse of the tumor (Chevillard et al., 1996; Zhou,

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P-glycoprotein Mediated Efflux Modulators of Plant Origin: A Short Review

Cited by 11 publications

References 38 publications

Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability

Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability

MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma

Overcoming vincristine resistance in cancer: Computational design and discovery of piperine‐inspired P‐glycoprotein inhibitors

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