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Статті в журналах з теми "P-glycoprotein inhibitors"

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Автор: Grafiati

Опубліковано: 10 грудня 2022

Оновлено: 28 січня 2023

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1

Gherbovet, Olga, María Concepción García Alvarez, Jérôme Bignon, and Fanny Roussi. "Original Vinca Derivatives: From P-Glycoprotein Substrates to P-Glycoprotein Inhibitors." Journal of Medicinal Chemistry 59, no. 23 (November 23, 2016): 10774–80. http://dx.doi.org/10.1021/acs.jmedchem.6b00525.

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2

Chae, Song Wha, Jaeok Lee, Jung Hyun Park, Youngjoo Kwon, Younghwa Na, and Hwa Jeong Lee. "Intestinal P-glycoprotein inhibitors, benzoxanthone analogues." Journal of Pharmacy and Pharmacology 70, no. 2 (December 13, 2017): 234–41. http://dx.doi.org/10.1111/jphp.12832.

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3

al-Shawi, M. K., I. L. Urbatsch, and A. E. Senior. "Covalent inhibitors of P-glycoprotein ATPase activity." Journal of Biological Chemistry 269, no. 12 (March 1994): 8986–92. http://dx.doi.org/10.1016/s0021-9258(17)37065-5.

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4

Kono, Yusuke, Iichiro Kawahara, Kohei Shinozaki, Ikuo Nomura, Honoka Marutani, Akira Yamamoto, and Takuya Fujita. "Characterization of P-Glycoprotein Inhibitors for Evaluating the Effect of P-Glycoprotein on the Intestinal Absorption of Drugs." Pharmaceutics 13, no. 3 (March 15, 2021): 388. http://dx.doi.org/10.3390/pharmaceutics13030388.

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Анотація:

For developing oral drugs, it is necessary to predict the oral absorption of new chemical entities accurately. However, it is difficult because of the involvement of efflux transporters, including P-glycoprotein (P-gp), in their absorption process. In this study, we conducted a comparative analysis on the inhibitory activities of seven P-gp inhibitors (cyclosporin A, GF120918, LY335979, XR9576, WK-X-34, VX-710, and OC144-093) to evaluate the effect of P-gp on drug absorption. GF120918, LY335979, and XR9576 significantly decreased the basal-to-apical transport of paclitaxel, a P-gp substrate, across Caco-2 cell monolayers. GF120918 also inhibited the basal-to-apical transport of mitoxantrone, a breast cancer resistance protein (BCRP) substrate, in Caco-2 cells, whereas LY335979 hardly affected the mitoxantrone transport. In addition, the absorption rate of paclitaxel after oral administration in wild-type mice was significantly increased by pretreatment with LY335979, and it was similar to that in mdr1a/1b knockout mice. Moreover, the absorption rate of topotecan, a BCRP substrate, in wild-type mice pretreated with LY335979 was similar to that in mdr1a/1b knockout mice but significantly lower than that in bcrp knockout mice. These results indicate that LY335979 has a selective inhibitory activity for P-gp, and would be useful for evaluating the contribution of P-gp to drug absorption.

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5

Pleban, Karin, and Gerhard Ecker. "Inhibitors of P-Glycoprotein - Lead Identification and Optimisation." Mini-Reviews in Medicinal Chemistry 5, no. 2 (February 1, 2005): 153–63. http://dx.doi.org/10.2174/1389557053402729.

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6

Yu, Jun, Peng Zhou, James Asenso, Xiao-Dan Yang, Chun Wang, and Wei Wei. "Advances in plant-based inhibitors of P-glycoprotein." Journal of Enzyme Inhibition and Medicinal Chemistry 31, no. 6 (March 2, 2016): 867–81. http://dx.doi.org/10.3109/14756366.2016.1149476.

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7

Srivalli, Kale Mohana Raghava, and P. K. Lakshmi. "Overview of P-glycoprotein inhibitors: a rational outlook." Brazilian Journal of Pharmaceutical Sciences 48, no. 3 (September 2012): 353–67. http://dx.doi.org/10.1590/s1984-82502012000300002.

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Анотація:

P-glycoprotein (P-gp), a transmembrane permeability glycoprotein, is a member of ATP binding cassette (ABC) super family that functions specifically as a carrier mediated primary active efflux transporter. It is widely distributed throughout the body and has a diverse range of substrates. Several vital therapeutic agents are substrates to P-gp and their bioavailability is lowered or a resistance is induced because of the protein efflux. Hence P-gp inhibitors were explored for overcoming multidrug resistance and poor bioavailability problems of the therapeutic P-gp substrates. The sensitivity of drug moieties to P-gp and vice versa can be established by various experimental models in silico, in vitro and in vivo. Ever since the discovery of P-gp, the research plethora identified several chemical structures as P-gp inhibitors. The aim of this review was to emphasize on the discovery and development of newer, inert, non-toxic, and more efficient, specifically targeting P-gp inhibitors, like those among the natural herb extracts, pharmaceutical excipients and formulations, and other rational drug moieties. The applications of cellular and molecular biology knowledge, in silico designed structural databases, molecular modeling studies and quantitative structure-activity relationship (QSAR) analyses in the development of novel rational P-gp inhibitors have also been mentioned.

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8

Chang, Cheng, Praveen M. Bahadduri, James E. Polli, Peter W. Swaan, and Sean Ekins. "Rapid Identification of P-glycoprotein Substrates and Inhibitors." Drug Metabolism and Disposition 34, no. 12 (September 22, 2006): 1976–84. http://dx.doi.org/10.1124/dmd.106.012351.

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9

Bogman, Katrijn, Anne-Kathrin Peyer, Michael Török, Ernst Küsters, and Jürgen Drewe. "HMG-CoA reductase inhibitors and P-glycoprotein modulation." British Journal of Pharmacology 132, no. 6 (March 2001): 1183–92. http://dx.doi.org/10.1038/sj.bjp.0703920.

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10

Tarasova, Nadya I., Rishi Seth, Sergey G. Tarasov, Teresa Kosakowska-Cholody, Christine A. Hrycyna, Michael M. Gottesman, and Christopher J. Michejda. "Transmembrane Inhibitors of P-Glycoprotein, an ABC Transporter." Journal of Medicinal Chemistry 48, no. 11 (June 2005): 3768–75. http://dx.doi.org/10.1021/jm049065t.

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11

Li-Blatter, Xiaochun, Pierluigi Nervi, and Anna Seelig. "Detergents as intrinsic P-glycoprotein substrates and inhibitors." Biochimica et Biophysica Acta (BBA) - Biomembranes 1788, no. 10 (October 2009): 2335–44. http://dx.doi.org/10.1016/j.bbamem.2009.07.010.

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12

Kim, Richard B. "Drugs as P-glycoprotein substrates, inhibitors, and inducers." Drug Metabolism Reviews 34, no. 1-2 (January 2002): 47–54. http://dx.doi.org/10.1081/dmr-120001389.

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13

Rehman, Saleha, Bushra Nabi, Mohammad Fazil, Saba Khan, Naimat Kalim Bari, Romi Singh, Shavej Ahmad, Varinder Kumar, Sanjula Baboota, and Javed Ali. "Role of P-Glycoprotein Inhibitors in the Bioavailability Enhancement of Solid Dispersion of Darunavir." BioMed Research International 2017 (2017): 1–17. http://dx.doi.org/10.1155/2017/8274927.

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Анотація:

Objective. The aim of the present study was to improve bioavailability of an important antiretroviral drug, Darunavir (DRV), which has low water solubility and poor intestinal absorption through solid dispersion (SD) approach incorporating polymer with P-glycoprotein inhibitory potential. Methods. A statistical approach where design of experiment (DoE) was used to prepare SD of DRV with incorporation of P-glycoprotein inhibitors. Using DoE, different methods of preparation, like melt, solvent evaporation, and spray drying method, utilizing carriers like Kolliphor TPGS and Soluplus were evaluated. The optimized SD was characterized by DSC, FTIR, XRD, and SEM and further evaluated for enhancement in absorption using everted gut sac model, effect of food on absorption of DRV, and in vivo prospect. Results and Discussion. DSC, FTIR, XRD, and SEM confirmed the amorphicity of drug in SD. Oral bioavailability studies revealed better absorption of DRV when given with food. Absorption studies and in vivo study findings demonstrated great potential of Kolliphor TPGS as P-glycoprotein inhibitor for increasing intestinal absorption and thus bioavailability of DRV. Conclusion. It is concluded that SD of DRV with the incorporation of Kolliphor TPGS was potential and promising approach in increasing bioavailability of DRV as well as minimizing its extrusion via P-glycoprotein efflux transporters.

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14

Dastvan, Reza, Smriti Mishra, Yelena B. Peskova, Robert K. Nakamoto, and Hassane S. Mchaourab. "Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors." Science 364, no. 6441 (May 16, 2019): 689–92. http://dx.doi.org/10.1126/science.aav9406.

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The ATP-binding cassette subfamily B member 1 (ABCB1) multidrug transporter P-glycoprotein plays a central role in clearance of xenobiotics in humans and is implicated in cancer resistance to chemotherapy. We used double electron electron resonance spectroscopy to uncover the basis of stimulation of P-glycoprotein adenosine 5′-triphosphate (ATP) hydrolysis by multiple substrates and illuminate how substrates and inhibitors differentially affect its transport function. Our results reveal that substrate-induced acceleration of ATP hydrolysis correlates with stabilization of a high-energy, post-ATP hydrolysis state characterized by structurally asymmetric nucleotide-binding sites. By contrast, this state is destabilized in the substrate-free cycle and by high-affinity inhibitors in favor of structurally symmetric nucleotide binding sites. Together with previous data, our findings lead to a general model of substrate and inhibitor coupling to P-glycoprotein.

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15

Grigoreva, T., A. Romanova, A. Sagaidak, S. Vorona, D. Novikova, and V. Tribulovich. "Mdm2 inhibitors as a platform for the design of P-glycoprotein inhibitors." Bioorganic & Medicinal Chemistry Letters 30, no. 18 (September 2020): 127424. http://dx.doi.org/10.1016/j.bmcl.2020.127424.

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16

Demeule, Michel, Alain Laplante, Arash Sepehr-Araé, Édith Beaulieu, Diana Averill-Bates, Roland M. Wenger, and Richard Béliveau. "Inhibition of P-glycoprotein by cyclosporin A analogues and metabolites." Biochemistry and Cell Biology 77, no. 1 (March 1, 1999): 47–58. http://dx.doi.org/10.1139/o99-011.

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The interaction between P-glycoprotein (P-gp) from membranes isolated from multidrug-resistant Chinese hamster ovary cells and cyclosporin A (CsA) analogues and its metabolites was characterized. Screening of these latter as chemosensitizers was performed using three different assays: (i) vinblastine uptake, (ii) photoaffinity labeling by [125I]iodoaryl azidoprazosin, and (iii) P-gp ATPase activity. Oxidation of the hydroxyl group at position 1 of CsA (200-096), CsG (215-834), or CsD (PSC-833) increased their inhibition of P-gp. CsA analogues (208-032, 208-183) modified at position 11 retained their ability to inhibit P-gp while analogues modified at position 2 (CsC and CsD) lost their efficiency. The inhibitions induced by metabolites of CsA were also compared to those obtained with CsG metabolites. From all the molecules tested, PSC-833 and 280-446 peptolide were the strongest inhibitors. Our results indicate that modifications of CsA analogues at position 1 and 2 are critical for their interaction with P-gp and that CsA metabolites retain a portion of the inhibitory activity of the parent drug.Key words: P-glycoprotein, cyclosporin A, vinblastine uptake, photolabeling, ATPase activity.

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17

Prié, Dominique, Sylviane Couette, Isabelle Fernandes, Caroline Silve, and Gérard Friedlander. "P-glycoprotein inhibitors stimulate renal phosphate reabsorption in rats." Kidney International 60, no. 3 (September 2001): 1069–76. http://dx.doi.org/10.1046/j.1523-1755.2001.0600031069.x.

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18

Bisi, Alessandra, Silvia Gobbi, Angela Rampa, Federica Belluti, Lorna Piazzi, Piero Valenti, Nora Gyemant, and Joseph Molnár. "New Potent P-Glycoprotein Inhibitors Carrying a Polycyclic Scaffold." Journal of Medicinal Chemistry 49, no. 11 (June 2006): 3049–51. http://dx.doi.org/10.1021/jm060056p.

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19

Zaja, Roko, Senka Terzić, Ivan Senta, Jovica Lončar, Marta Popović, Marijan Ahel, and Tvrtko Smital. "Identification of P-Glycoprotein Inhibitors in Contaminated Freshwater Sediments." Environmental Science & Technology 47, no. 9 (April 18, 2013): 4813–21. http://dx.doi.org/10.1021/es400334t.

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20

Alcantara, Laura M., Junwon Kim, Carolina B. Moraes, Caio H. Franco, Kathrin D. Franzoi, Sukjun Lee, Lucio H. Freitas-Junior, and Lawrence S. Ayong. "Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites." Experimental Parasitology 134, no. 2 (June 2013): 235–43. http://dx.doi.org/10.1016/j.exppara.2013.03.022.

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21

Yasuda, Kazuto, Lu-bin Lan, Dominique Sanglard, Katryn Furuya, John D. Schuetz, and Erin G. Schuetz. "Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein." Journal of Pharmacology and Experimental Therapeutics 303, no. 1 (October 1, 2002): 323–32. http://dx.doi.org/10.1124/jpet.102.037549.

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22

Xia, Mengmeng, Yajing Fang, Weiwei Cao, Fuqiang Liang, Siyi Pan, and Xiaoyun Xu. "Quantitative Structure–Activity Relationships for the Flavonoid-Mediated Inhibition of P-Glycoprotein in KB/MDR1 Cells." Molecules 24, no. 9 (April 27, 2019): 1661. http://dx.doi.org/10.3390/molecules24091661.

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P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure–activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q2) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3′-OH, 4′-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp.

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23

Kopecka, Joanna, Martina Godel, Silvia Dei, Roberta Giampietro, Dimas Carolina Belisario, Muhlis Akman, Marialessandra Contino, Elisabetta Teodori, and Chiara Riganti. "Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death." Cells 9, no. 4 (April 22, 2020): 1033. http://dx.doi.org/10.3390/cells9041033.

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Doxorubicin is a strong inducer of immunogenic cell death (ICD), but it is ineffective in P-glycoprotein (Pgp)-expressing cells. Indeed, Pgp effluxes doxorubicin and impairs the immunesensitizing functions of calreticulin (CRT), an “eat-me” signal mediating ICD. It is unknown if classical Pgp inhibitors, designed to reverse chemoresistance, may restore ICD. We addressed this question by using Pgp-expressing cancer cells, treated with Tariquidar, a clinically approved Pgp inhibitor, and R-3 compound, a N,N-bis(alkanol)amine aryl ester derivative with the same potency of Tariquidar as Pgp inhibitor. In Pgp-expressing/doxorubicin-resistant cells, Tariquidar and R-3 increased doxorubicin accumulation and toxicity, reduced Pgp activity, and increased CRT translocation and ATP and HMGB1 release. Unexpectedly, only R-3 promoted phagocytosis by dendritic cells and activation of antitumor CD8+T-lymphocytes. Although Tariquidar did not alter the amount of Pgp present on cell surface, R-3 promoted Pgp internalization and ubiquitination, disrupting its interaction with CRT. Pgp knock-out restores doxorubicin-induced ICD in MDA-MB-231/DX cells that recapitulated the phenotype of R-3-treated cells. Our work demonstrates that plasma membrane-associated Pgp prevents a complete ICD notwithstanding the release of ATP and HMGB1, and the exposure of CRT. Pharmacological compounds reducing Pgp activity and amount may act as promising chemo- and immunesensitizing agents.

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24

Miyata, Yukio, Yasushi Asano, and Shigeaki Muto. "Effects of P-glycoprotein on cell volume regulation in mouse proximal tubule." American Journal of Physiology-Renal Physiology 280, no. 5 (May 1, 2001): F829—F837. http://dx.doi.org/10.1152/ajprenal.2001.280.5.f829.

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The role of P-glycoprotein (P-gp) in cell volume regulation was examined in isolated nonperfused proximal tubule S2 segments from wild-type (WT) mice and those in which both mdr1a and mdr1b genes were knocked out (KO). When the osmolality of the bathing solution was rapidly decreased from 300 to 180 mosmol/kgH2O, the tubules from both the WT and KO mice exhibited regulatory volume decrease (RVD) by a similar magnitude after the initial cell swelling. The peritubular addition of two P-pg inhibitors (verapamil and cyclosporin A) to either group of the tubules had no effect on RVD. When the tubules from the WT mice were rapidly exposed to a hyperosmotic solution (500 mosmol/kgH2O) including 200 mM mannitol, they abruptly shrank to 82.1% of their control volume but remained in a shrunken state during the experimental period, indicating a lack of regulatory volume increase (RVI). The addition of the two P-gp inhibitors, but not the inhibitor of the renal organic cation transport system (tetraethylammonium), to the tubules from the WT mice resulted in RVI. Surprisingly, when the tubules from the KO mice were exposed to the hyperosmotic solution, they abruptly shrank to 79.9% of their control volume, and then gradually swelled to 87.7% of their control volume, showing RVI. However, exposure of the tubules from the KO mice to the hyperosmotic solution in the presence of the two P-gp inhibitors had no effect on RVI. When the tubules of the WT mice were exposed to the hyperosmotic solution including either of the two P-gp inhibitors, in the absence of peritubular Na+ or in the presence of peritubular ethylisopropylamiloride (EIPA; the specific inhibitor of Na+/H+ exchange), they did not exhibit RVI. In the tubules of the KO mice, both removing peritubular Na+and adding peritubular EIPA inhibited RVI induced by the hyperosmotic solution. We conclude that 1) in mouse proximal tubule, P-gp modulates RVI during hyperosmotic stress but not RVD during hyposmotic stress and 2) basolateral membrane Na+/H+ exchange partly contributes to the P-gp-induced modulation of RVI under hyperosmotic stress.

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25

Wang, Pei-Hua, Yi-Shu Tu, and Yufeng J. Tseng. "PgpRules: a decision tree based prediction server for P-glycoprotein substrates and inhibitors." Bioinformatics 35, no. 20 (March 27, 2019): 4193–95. http://dx.doi.org/10.1093/bioinformatics/btz213.

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Abstract Summary P-glycoprotein (P-gp) is a member of ABC transporter family that actively pumps xenobiotics out of cells to protect organisms from toxic compounds. P-gp substrates can be easily pumped out of the cells to reduce their absorption; conversely P-gp inhibitors can reduce such pumping activity. Hence, it is crucial to know if a drug is a P-gp substrate or inhibitor in view of pharmacokinetics. Here we present PgpRules, an online P-gp substrate and P-gp inhibitor prediction server with ruled-sets. The two models were built using classification and regression tree algorithm. For each compound uploaded, PgpRules not only predicts whether the compound is a P-gp substrate or a P-gp inhibitor, but also provides the rules containing chemical structural features for further structural optimization. Availability and implementation PgpRules is freely accessible at https://pgprules.cmdm.tw/. Supplementary information Supplementary data are available at Bioinformatics online.

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26

Arora, Neha. "Structural Mapping of Inhibitors Binding Sites on P-glycoprotein: Mechanism of Inhibition of P-Glycoprotein by Herbal Isoflavones." International Journal of Biochemistry Research & Review 3, no. 4 (January 10, 2013): 421–35. http://dx.doi.org/10.9734/ijbcrr/2013/3268.

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27

Kurnik, Daniel, Gbenga G. Sofowora, John P. Donahue, Usha B. Nair, Grant R. Wilkinson, Alastair J. J. Wood, and Mordechai Muszkat. "Tariquidar, a Selective P-glycoprotein Inhibitor, Does Not Potentiate Loperamide’s Opioid Brain Effects in Humans despite Full Inhibition of Lymphocyte P-glycoprotein." Anesthesiology 109, no. 6 (December 1, 2008): 1092–99. http://dx.doi.org/10.1097/aln.0b013e31818d8f28.

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Background Loperamide, a potent opioid, has been used as an in vivo probe to assess P-glycoprotein activity at the blood-brain barrier, because P-glycoprotein inhibition allows loperamide to cross the blood-brain barrier and exert its central opioid effects. In humans, studies with nonselective and moderately potent inhibitors resulted in mild opioid effects but were confounded by the concurrent inhibition of loperamide's metabolism. The authors studied the effect of the highly selective, potent P-glycoprotein inhibitor tariquidar on loperamide's central opioid effects. Methods In a randomized, double-blind, crossover study, nine healthy subjects received on 2 study days oral loperamide (32 mg) followed by an intravenous infusion of either tariquidar (150 mg) or placebo. Central opioid effects (pupil diameter, sedation) were measured for 12 h, and blood samples were drawn up to 48 h after drug administration to determine plasma loperamide concentrations and ex vivo P-glycoprotein activity in T lymphocytes. Values for pupil diameter and loperamide concentrations were plotted over time, and the areas under the curves on the tariquidar and placebo study day were compared within each subject. Results Tariquidar did not significantly affect loperamide's central effects (median reduction in pupil diameter area under the curve, 6.9% [interquartile range, -1.4 to 12.1%]; P = 0.11) or plasma loperamide concentrations (P = 0.12) but profoundly inhibited P-glycoprotein in lymphocytes by 93.7% (95% confidence interval, 92.0-95.3%). Conclusion These results suggest that despite full inhibition of lymphocyte P-glycoprotein, the selective P-glycoprotein inhibitor tariquidar does not potentiate loperamide's opioid brain effects in humans.

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28

Westwell, Andrew D. "Novel telomerase inhibitors targeting quadreplex DNA; antitumour benzothiazoles; P-Glycoprotein efflux pump inhibitors; new topoisomerase inhibitors." Drug Discovery Today 7, no. 9 (May 2002): 528–31. http://dx.doi.org/10.1016/s1359-6446(02)02247-x.

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29

Liu, Hongming, Zhiguo Ma, and Baojian Wu. "Structure-activity relationships andin silicomodels of P-glycoprotein (ABCB1) inhibitors." Xenobiotica 43, no. 11 (April 25, 2013): 1018–26. http://dx.doi.org/10.3109/00498254.2013.791003.

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30

Bansal, Tripta, Manu Jaggi, Roop Khar, and Sushama Talegaonkar. "Status of Flavonols as P-Glycoprotein Inhibitors in Cancer Chemotherapy." Current Cancer Therapy Reviews 5, no. 2 (May 1, 2009): 89–99. http://dx.doi.org/10.2174/157339409788166742.

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31

Wang, R. B., C. L. Kuo, L. L. Lien, and E. J. Lien. "Structure-activity relationship: analyses of p-glycoprotein substrates and inhibitors." Journal of Clinical Pharmacy and Therapeutics 28, no. 3 (June 2003): 203–28. http://dx.doi.org/10.1046/j.1365-2710.2003.00487.x.

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32

Leopoldo, Marcello, Patrizia Nardulli, Marialessandra Contino, Francesco Leonetti, Gert Luurtsema, and Nicola Antonio Colabufo. "An updated patent review on P-glycoprotein inhibitors (2011-2018)." Expert Opinion on Therapeutic Patents 29, no. 6 (May 17, 2019): 455–61. http://dx.doi.org/10.1080/13543776.2019.1618273.

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33

Jakubowski, Piotr, Michał Majewski, Piotr Podlasz, Anna Jakimiuk, and Natalia Kasica. "P-glycoprotein inhibitors modulate levetiracetam effects in zebrafish epilepsy model." Pharmacological Reports 67 (September 2015): 23. http://dx.doi.org/10.1016/j.pharep.2015.06.071.

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34

Mollazadeh, Shirin, Amirhossein Sahebkar, Farzin Hadizadeh, Javad Behravan, and Sepideh Arabzadeh. "Structural and functional aspects of P-glycoprotein and its inhibitors." Life Sciences 214 (December 2018): 118–23. http://dx.doi.org/10.1016/j.lfs.2018.10.048.

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35

Zeino, Maen, Malte S. Paulsen, Martin Zehl, Ernst Urban, Brigitte Kopp, and Thomas Efferth. "Identification of new P-glycoprotein inhibitors derived from cardiotonic steroids." Biochemical Pharmacology 93, no. 1 (January 2015): 11–24. http://dx.doi.org/10.1016/j.bcp.2014.10.009.

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36

Crivori, Patrizia, Benedetta Reinach, Daniele Pezzetta, and Italo Poggesi. "Computational Models for Identifying Potential P-Glycoprotein Substrates and Inhibitors." Molecular Pharmaceutics 3, no. 1 (December 8, 2005): 33–44. http://dx.doi.org/10.1021/mp050071a.

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37

Pan, Xianchao, Li Chao, Wen Tan, Li Yang, Roman Podraza, and Hu Mei. "Emerging chemical patterns applied to prediction of P-glycoprotein inhibitors." Chemometrics and Intelligent Laboratory Systems 137 (October 2014): 140–45. http://dx.doi.org/10.1016/j.chemolab.2014.06.017.

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38

Pan, Qiangrong, Qinghua Lu, Kun Zhang, and Xun Hu. "Dibenzocyclooctadiene lingnans: a class of novel inhibitors of P-glycoprotein." Cancer Chemotherapy and Pharmacology 58, no. 1 (October 18, 2005): 99–106. http://dx.doi.org/10.1007/s00280-005-0133-1.

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39

Dong, Jinyun, Zuodong Qin, Wei-Dong Zhang, Gang Cheng, Assaraf G. Yehuda, Charles R. Ashby, Zhe-Sheng Chen, Xiang-Dong Cheng, and Jiang-Jiang Qin. "Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update." Drug Resistance Updates 49 (March 2020): 100681. http://dx.doi.org/10.1016/j.drup.2020.100681.

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40

Wang, Zhen, Iris L. K. Wong, Fu Xing Li, Chao Yang, Zhen Liu, Tao Jiang, Ting Fu Jiang, Larry M. C. Chow, and Sheng Biao Wan. "Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors." Bioorganic & Medicinal Chemistry 23, no. 17 (September 2015): 5566–73. http://dx.doi.org/10.1016/j.bmc.2015.07.027.

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41

Chen, Lei, Youyong Li, Huidong Yu, Liling Zhang, and Tingjun Hou. "Computational models for predicting substrates or inhibitors of P-glycoprotein." Drug Discovery Today 17, no. 7-8 (April 2012): 343–51. http://dx.doi.org/10.1016/j.drudis.2011.11.003.

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42

Kadioglu, Onat, and Thomas Efferth. "A Machine Learning-Based Prediction Platform for P-Glycoprotein Modulators and Its Validation by Molecular Docking." Cells 8, no. 10 (October 21, 2019): 1286. http://dx.doi.org/10.3390/cells8101286.

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Анотація:

P-glycoprotein (P-gp) is an important determinant of multidrug resistance (MDR) because its overexpression is associated with increased efflux of various established chemotherapy drugs in many clinically resistant and refractory tumors. This leads to insufficient therapeutic targeting of tumor populations, representing a major drawback of cancer chemotherapy. Therefore, P-gp is a target for pharmacological inhibitors to overcome MDR. In the present study, we utilized machine learning strategies to establish a model for P-gp modulators to predict whether a given compound would behave as substrate or inhibitor of P-gp. Random forest feature selection algorithm-based leave-one-out random sampling was used. Testing the model with an external validation set revealed high performance scores. A P-gp modulator list of compounds from the ChEMBL database was used to test the performance, and predictions from both substrate and inhibitor classes were selected for the last step of validation with molecular docking. Predicted substrates revealed similar docking poses than that of doxorubicin, and predicted inhibitors revealed similar docking poses than that of the known P-gp inhibitor elacridar, implying the validity of the predictions. We conclude that the machine-learning approach introduced in this investigation may serve as a tool for the rapid detection of P-gp substrates and inhibitors in large chemical libraries.

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43

Sugie, Masami, Emiko Asakura, Ying Lan Zhao, Shoko Torita, Masayuki Nadai, Kenji Baba, Kiyoyuki Kitaichi, Kenji Takagi, Kenzo Takagi, and Takaaki Hasegawa. "Possible Involvement of the Drug Transporters P Glycoprotein and Multidrug Resistance-Associated Protein Mrp2 in Disposition of Azithromycin." Antimicrobial Agents and Chemotherapy 48, no. 3 (March 2004): 809–14. http://dx.doi.org/10.1128/aac.48.3.809-814.2004.

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ABSTRACT P glycoprotein and multidrug resistance-associated protein 2 (Mrp2), ATP-dependent membrane transporters, exist in a variety of normal tissues and play important roles in the disposition of various drugs. The present study seeks to clarify the contribution of P glycoprotein and/or Mrp2 to the disposition of azithromycin in rats. The disappearance of azithromycin from plasma after intravenous administration was significantly delayed in rats treated with intravenous injection of cyclosporine, a P-glycoprotein inhibitor, but was normal in rats pretreated with intraperitoneal injection erythromycin, a CYP3A4 inhibitor. When rats received an infusion of azithromycin, cyclosporine and probenecid, a validated Mrp2 inhibitor, significantly decreased the steady-state biliary clearance of azithromycin to 5 and 40% of the corresponding control values, respectively. However, both inhibitors did not alter the renal clearance of azithromycin, suggesting the lack of renal tubular secretion of azithromycin. Tissue distribution experiments showed that azithromycin is distributed largely into the liver, kidney, and lung, whereas both inhibitors did not alter the tissue-to-plasma concentration ratio of azithromycin. Significant reduction in the biliary excretion of azithromycin was observed in Eisai hyperbilirubinemic rats, which have a hereditary deficiency in Mrp2. An in situ closed-loop experiment showed that azithromycin was excreted from the blood into the gut lumen, and the intestinal clearance of azithromycin was significantly decreased by the presence of cyclosporine in the loop. These results suggest that azithromycin is a substrate for both P glycoprotein and Mrp2 and that the biliary and intestinal excretion of azithromycin is mediated via these two drug transporters.

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44

Sergent, Jacques-Aurélien, Hilarion Mathouet, Christian Hulen, Pedro Lameiras, Marc Feuilloley, Abdelhakim Elomri, and Nour-Eddine Lomri. "Effects of Two Natural Bisbenzylisoquinolines, Curine and Guattegaumerine, Extracted from Isolona hexaloba on Rhodamine Efflux by Abcb1b from Rat Glycocholic-Acid-Resistant Hepatocarcinoma Cells." Molecules 27, no. 9 (May 9, 2022): 3030. http://dx.doi.org/10.3390/molecules27093030.

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Анотація:

To develop new therapeutic molecules, it is essential to understand the biological effects and targets of clinically relevant compounds. In this article, we describe the extraction and characterization of two alkaloids from the roots of Isolona hexaloba—curine and guattegaumerine. The effect of these alkaloids on the multidrug efflux pump ABCB1 (MDR1/P-Glycoprotein) and their antiproliferative properties were studied. Compared to verapamil, a widely used inhibitor of P-gp, curine and guattegaumerine were found to be weak inhibitors of MDR1/P-Glycoprotein. The highest inhibition of efflux produced by verapamil disappeared in the presence of curine or guattegaumerine as competitors, and the most pronounced effect was achieved with curine. Altogether, this work has provided new insights into the biological effects of these alkaloids on the rat Mdr1b P-gp efflux mechanism and would be beneficial in the design of potent P-gp inhibitors.

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45

Xing, Juan, Shuheng Huang, Yu Heng, Hu Mei, and Xianchao Pan. "Computational Insights into Allosteric Conformational Modulation of P-Glycoprotein by Substrate and Inhibitor Binding." Molecules 25, no. 24 (December 18, 2020): 6006. http://dx.doi.org/10.3390/molecules25246006.

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Анотація:

The ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) is a physiologically essential membrane protein that protects many tissues against xenobiotic molecules, but limits the access of chemotherapeutics into tumor cells, thus contributing to multidrug resistance. The atomic-level mechanism of how substrates and inhibitors differentially affect the ATP hydrolysis by P-gp remains to be elucidated. In this work, atomistic molecular dynamics simulations in an explicit membrane/water environment were performed to explore the effects of substrate and inhibitor binding on the conformational dynamics of P-gp. Distinct differences in conformational changes that mainly occurred in the nucleotide-binding domains (NBDs) were observed from the substrate- and inhibitor-bound simulations. The binding of rhodamine-123 can increase the probability of the formation of an intermediate conformation, in which the NBDs were closer and better aligned, suggesting that substrate binding may prime the transporter for ATP hydrolysis. By contrast, the inhibitor QZ-Leu stabilized NBDs in a much more separated and misaligned conformation, which may result in the deficiency of ATP hydrolysis. The significant differences in conformational modulation of P-gp by substrate and inhibitor binding provided a molecular explanation of how these small molecules exert opposite effects on the ATPase activity. A further structural analysis suggested that the allosteric communication between transmembrane domains (TMDs) and NBDs was primarily mediated by two intracellular coupling helices. Our computational simulations provide not only valuable insights into the transport mechanism of P-gp substrates, but also for the molecular design of P-gp inhibitors.

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46

Katayama, Kazuhiro, Kohji Noguchi, and Yoshikazu Sugimoto. "Regulations of P-Glycoprotein/ABCB1/MDR1 in Human Cancer Cells." New Journal of Science 2014 (May 20, 2014): 1–10. http://dx.doi.org/10.1155/2014/476974.

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Multidrug resistance (MDR) in cancer cells is a phenotype whereby cells display reduced sensitivity to anticancer drugs, based on a variety of mechanisms, including an increase in drug efflux, the reduction of drug uptake, the activation of cell growth and survival signaling, the promotion of DNA repair, and the inhibition of apoptosis signaling. Increased expression of the plasma membrane drug efflux pumps, the ATP-binding cassette (ABC) transporters, is involved in MDR. P-Glycoprotein/ABCB1 is a member of the ABC transporter family, and facilitates the efflux of various anticancer drugs, including anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, and kinase inhibitors, from cells. P-Glycoprotein is also expressed in normal tissues and cells, including the kidney, liver, colon, and adrenal gland, to transport and/or secrete substrates and at the blood-brain, blood-placenta, and blood-testis barriers to protect these tissues from toxic substances. To understand the mechanistic functions of P-glycoprotein and to overcome MDR, investigators have identified the substrates and competitive inhibitors of P-glycoprotein. Recently, we and other groups reported associations between cellular signaling pathways and the expression, stability, degradation, localization, and activity of P-glycoprotein. The present review summarizes the currently available information about the transcriptional and posttranslational regulation of P-glycoprotein expression and function.

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47

Miller, David S., Caroline R. Sussman, and J. Larry Renfro. "Protein kinase C regulation of p-glycoprotein-mediated xenobiotic secretion in renal proximal tubule." American Journal of Physiology-Renal Physiology 275, no. 5 (November 1, 1998): F785—F795. http://dx.doi.org/10.1152/ajprenal.1998.275.5.f785.

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Fluorescence microscopy, fluorescent substrates [daunomycin and a fluorescent cyclosporin A (CSA) derivative] and digital image analysis were used to examine the role of protein kinase C (PKC) in the control of p-glycoprotein in killifish renal proximal tubules. PKC activators, phorbol ester (phorbol 12-myristate 13-acetate, PMA) and dioctylglycerol, reduced luminal drug accumulation, and protein kinase inhibitors, staurosporine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), increased luminal accumulation; a PMA analog that does not activate PKC was without effect. PMA effects were blocked by staurosporine. The increase in luminal fluorescence caused by staurosporine was blocked by the p-glycoprotein substrate, CSA, indicating that this component of transport was indeed mediated by p-glycoprotein. Neither PMA, dioctylglycerol, nor protein kinase inhibitors altered cellular drug accumulation. Finally, in primary cultures of flounder proximal tubule cells, PMA decreased transepithelial [3H]daunomycin secretion. This pharmacological approach demonstrates that in teleost renal proximal tubule, p-glycoprotein-mediated xenobiotic secretion is negatively correlated with changes in PKC activity, a finding that conflicts with results from studies using mammalian tumor cells that express p-glycoprotein.

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48

RAGGERS, René J., Ilse VOGELS, and Gerrit van MEER. "Multidrug-resistance P-glycoprotein (MDR1) secretes platelet-activating factor." Biochemical Journal 357, no. 3 (July 25, 2001): 859–65. http://dx.doi.org/10.1042/bj3570859.

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Анотація:

The human multidrug-resistance (MDR1) P-glycoprotein (Pgp) is an ATP-binding-cassette transporter (ABCB1) that is ubiquitously expressed. Often its concentration is high in the plasma membrane of cancer cells, where it causes multidrug resistance by pumping lipophilic drugs out of the cell. In addition, MDR1 Pgp can transport analogues of membrane lipids with shortened acyl chains across the plasma membrane. We studied a role for MDR1 Pgp in transport to the cell surface of the signal-transduction molecule platelet-activating factor (PAF). PAF is the natural short-chain phospholipid 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. [14C]PAF synthesized intracellularly from exogenous alkylacetylglycerol and [14C]choline became accessible to albumin in the extracellular medium of pig kidney epithelial LLC-PK1 cells in the absence of vesicular transport. Its translocation across the apical membrane was greatly stimulated by the expression of MDR1 Pgp, and inhibited by the MDR1 inhibitors PSC833 and cyclosporin A. Basolateral translocation was not stimulated by expression of the basolateral drug transporter MRP1 (ABCC1). It was insensitive to the MRP1 inhibitor indomethacin and to depletion of GSH which is required for MRP1 activity. While efficient transport of PAF across the apical plasma membrane may be physiologically relevant in MDR1-expressing epithelia, PAF secretion in multidrug-resistant tumours may stimulate angiogenesis and thereby tumour growth.

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49

Marques, Sérgio M., Lucie Šupolíková, Lenka Molčanová, Karel Šmejkal, David Bednar, and Iva Slaninová. "Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance." Biomedicines 9, no. 4 (March 30, 2021): 357. http://dx.doi.org/10.3390/biomedicines9040357.

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Анотація:

Multidrug resistance (MDR) is a common problem when fighting cancer with chemotherapy. P-glycoprotein (P-gp, or MDR1) is an active pump responsible for the efflux of xenobiotics out of the cell, including anti-cancer drugs. It is a validated target against MDR. No crystal structure of the human P-gp is available to date, and only recently several cryo-EM structures have been solved. In this paper, we present a comprehensive computational approach that includes constructing the full-length three-dimensional structure of the human P-gp and its refinement using molecular dynamics. We assessed its flexibility and conformational diversity, compiling a dynamical ensemble that was used to dock a set of lignan compounds, previously reported as active P-gp inhibitors, and disclose their binding modes. Based on the statistical analysis of the docking results, we selected a system for performing the structure-based virtual screening of new potential P-gp inhibitors. We tested the method on a library of 87 natural flavonoids described in the literature, and 10 of those were experimentally assayed. The results reproduced the theoretical predictions only partially due to various possible factors. However, at least two of the predicted natural flavonoids were demonstrated to be effective P-gp inhibitors. They were able to increase the accumulation of doxorubicin inside the human promyelocytic leukemia HL60/MDR cells overexpressing P-gp and potentiate the antiproliferative activity of this anti-cancer drug.

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50

Mora Lagares, Liadys, Nikola Minovski, and Marjana Novič. "Multiclass Classifier for P-Glycoprotein Substrates, Inhibitors, and Non-Active Compounds." Molecules 24, no. 10 (May 25, 2019): 2006. http://dx.doi.org/10.3390/molecules24102006.

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Анотація:

P-glycoprotein (P-gp) is a transmembrane protein that actively transports a wide variety of chemically diverse compounds out of the cell. It is highly associated with the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of drugs/drug candidates and contributes to decreasing toxicity by eliminating compounds from cells, thereby preventing intracellular accumulation. Therefore, in the drug discovery and toxicological assessment process it is advisable to pay attention to whether a compound under development could be transported by P-gp or not. In this study, an in silico multiclass classification model capable of predicting the probability of a compound to interact with P-gp was developed using a counter-propagation artificial neural network (CP ANN) based on a set of 2D molecular descriptors, as well as an extensive dataset of 2512 compounds (1178 P-gp inhibitors, 477 P-gp substrates and 857 P-gp non-active compounds). The model provided a good classification performance, producing non error rate (NER) values of 0.93 for the training set and 0.85 for the test set, while the average precision (AvPr) was 0.93 for the training set and 0.87 for the test set. An external validation set of 385 compounds was used to challenge the model’s performance. On the external validation set the NER and AvPr values were 0.70 for both indices. We believe that this in silico classifier could be effectively used as a reliable virtual screening tool for identifying potential P-gp ligands.

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