Mechanisms and therapeutic potential of inhibiting drug efflux transporters

Klinke, Anna; Krajcsi, Péter

doi:10.1517/17425255.2015.1028917

Cited by 18 publications

(9 citation statements)

References 118 publications

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“…The CNS protective effect of BBB makes it quite difficult to treat brain malignancies or brain metastases, whereas the peripheral diseases are well controlled [213]. The CNS barrier can be partially overcome in the case of efflux transporter substrates by modulation of transporter proteins (e.g., P-gp or Mdr1).…”

Section: Efflux Transporter Inhibitionmentioning

confidence: 99%

Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

2019

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Treatment of certain central nervous system disorders, including different types of cerebral malignancies, is limited by traditional oral or systemic administrations of therapeutic drugs due to possible serious side effects and/or lack of the brain penetration and, therefore, the efficacy of the drugs is diminished. During the last decade, several new technologies were developed to overcome barrier properties of cerebral capillaries. This review gives a short overview of the structural elements and anatomical features of the blood–brain barrier. The various in vitro (static and dynamic), in vivo (microdialysis), and in situ (brain perfusion) blood–brain barrier models are also presented. The drug formulations and administration options to deliver molecules effectively to the central nervous system (CNS) are presented. Nanocarriers, nanoparticles (lipid, polymeric, magnetic, gold, and carbon based nanoparticles, dendrimers, etc.), viral and peptid vectors and shuttles, sonoporation and microbubbles are briefly shown. The modulation of receptors and efflux transporters in the cell membrane can also be an effective approach to enhance brain exposure to therapeutic compounds. Intranasal administration is a noninvasive delivery route to bypass the blood–brain barrier, while direct brain administration is an invasive mode to target the brain region with therapeutic drug concentrations locally. Nowadays, both technological and mechanistic tools are available to assist in overcoming the blood–brain barrier. With these techniques more effective and even safer drugs can be developed for the treatment of devastating brain disorders.

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Section: Efflux Transporter Inhibitionmentioning

confidence: 99%

Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

2019

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“…In past decades, ATP‐dependent efflux transporters, such as P‐glycoprotein (P‐gp), multidrug resistance‐associated protein (MRP) and breast cancer resistance protein (BCRP), have been shown to be actively involved in the absorption, distribution, metabolism, excretion and in drug–drug and drug–food interactions of orally administered drugs (Cheng, Wu, Ping, Wang, & Lu, ; Dahan, Sabit, & Amidon, ; Li et al, ; Li, de Graaf, de Jager, & Groothuis, ; Matsson, Pedersen, Norinder, Bergstrom, & Artursson, ). These transporters could limit the absorption of substrates by actively excreting their substrates back into the gut lumen (Klukovits & Krajcsi, ; Li et al, ). Besides this, multiple efflux pumps influence drug metabolism in the intestine, on the one hand by preventing product inhibition of the metabolic enzymes by active excretion of the metabolites, and on the other hand by controlling the accessibility of parent drugs to the metabolizing enzymes (Lan, Dalton, & Schuetz, ; Siissalo & Heikkinen, ).…”

Section: Introductionmentioning

confidence: 99%

Biopharmaceutics classification and intestinal absorption of chikusetsusaponin IVa

Zhang

Liu

2019

Biopharm & Drug Disp

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The objective of this study was to investigate the absorption behavior of chikusetsusaponin IVa (CHS-IVa) in the rat intestine using single-pass intestinal perfusion (SPIP) and to classify CHS-IVa into the biopharmaceutics classification system (BCS). The equilibrium solubility of CHS-IVa was determined by the shaker method.The absorption mechanism of CHS-IVa in the intestine was studied by comparing the P eff of different concentrations of CHS-IVa. The intestinal site dependence of CHS-IVa absorption was studied by comparing the P eff of the same concentration of CHS-IVa in different intestinal segments. The relationship between CHS-IVa and intestinal efflux protein was studied by perfusion with an efflux protein inhibitor.The permeability of CHS-IVa was investigated by comparing the P eff of CHS-IVa and the reported value. The solubility of CHS-IVa over the pH range 1.0-7.5 was 14.4 ± 0.29 to 16.9 ± 0.34 mg/ml. The P eff of CHS-IVa in the duodenum was 1.76 × 10 −3 to 2.00 × 10 −3 cm/min. The P eff of CHS-IVa in the jejunum was 1.26 × 10 −3 to 1.39 × 10 −3 cm/min. The P eff of CHS-IVa in the ileum was 1.25 × 10 −3 to 1.31 × 10 −3 cm/min. The P eff of CHS-IVa in the colon was 1.02 × 10 −3 to 1.08 × 10 −3 cm/min. There was no statistical difference of the P eff in the four segments at different CHS-IVa concentrations. The P eff of CHS-IVa (0.07, 0.7 and 7.0 mg/ml) were all notably smaller than the reported P eff (3.00 × 10 −3 cm/min) in the jejunum. The P eff of CHS-IVa was not influenced by verapamil (P-gp inhibitor), indomethacin (MRP inhibitor) and pantoprazole (BCRP inhibitor). CHS-IVa was classified as high solubility, low permeability and BCS III. The main absorptive tracts were the upper intestinal tracts and the rank order of intestinal permeability was duodenum > jejunum ≈ ileum > colon. The transport mechanism of CHS-IVa in all intestinal segments might be primarily passive transport. CHS-IVa was not a substrate of P-gp, MRP and BCRP.

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“…Thus, it is thought that the development of novel treatment strategies exploiting collateral sensitivity could improve cancer treatment from refractory tumors by being resensitized to drugs through the selective killing of MDR cells, or by preventing the development of the MDR phenotype through coadministration during chemotherapy. This is a widely observed phenomenon, found not only in P-gp-expressing cancer cells, but also in tumors overexpressing other ABC transporters such as the multidrug resistance protein 1 (MRP1/ABCC1) and the breast cancer resistance protein (BCRP/ABCG2) [7].…”

Section: Introductionmentioning

confidence: 94%

Triterpenoids from Momordica balsamina with a Collateral Sensitivity Effect for Tackling Multidrug Resistance in Cancer Cells

et al. 2018

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The collateral sensitivity effect is among the most promising strategies for overcoming multidrug resistance in cancer. In this work, 28 cucurbitane-type triterpenoids (1: -28: ), previously isolated from the African medicinal plant and its derivatives, were evaluated for their collateral sensitivity effect on three different human cancer entities, gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29), each with two different multidrug-resistant variants. One was selected for its resistance to daunorubicin (EPG85-257RDB, EPP85-181RDB, HT-29RDB) and the other was selected for its resistance to mitoxantrone (EPG85-257RNOV, EPP85-181RNOV, HT-29RNOV). On gastric cell lines, the best results were obtained for compounds 3: and 10: , which exhibited a collateral sensitivity effect together with high antiproliferative activity. In turn, on colon cancer cell lines, the best multidrug resistance-selective antiproliferative effects were observed for derivatives 11, 13: , and 15: , which showed collateral sensitivity effects against both resistant variants. Compounds 11: and 3: were also the most selective against the multidrug resistance pancreatic cells lines. Some compounds, such 6, 10, 11: and 15: , were previously found to be strong P-glycoprotein modulators, thus highlighting their potential as promising leads for overcoming multidrug resistance in cancer cells.

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Mechanisms and therapeutic potential of inhibiting drug efflux transporters

Cited by 18 publications

References 118 publications

Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

Biopharmaceutics classification and intestinal absorption of chikusetsusaponin IVa

Triterpenoids from Momordica balsamina with a Collateral Sensitivity Effect for Tackling Multidrug Resistance in Cancer Cells

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