Excipients to Inhibit Efflux Transporters: History
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Contributor:
Xiaoqing Miao
,
Rong Lu
,

Efflux transporters distributed at the apical side of human intestinal epithelial cells actively transport drugs from the enterocytes to the intestinal lumen, which could lead to extremely poor absorption of drugs by oral administration. Efflux transporters in the gastrointestinal tract mainly include P-gp, MRPs and BCRP.

  • efflux transporters
  • oral drug absorption
  • functional excipients
  • inhibitors

1. Introduction

Oral administration is the most practical and popular approach due to its good patient compliance, convenience and low cost compared to other administration routes, and it could accomplish the purpose of local and systemic treatment. However, the oral absorption of some drugs is limited due to poor solubility [1][2], poor intestinal permeability [3], liver first-pass effect and particularly intestinal drug efflux mediated by efflux transporters [4].
Efflux transporters in the gastrointestinal tract mainly include P-gp, MRPs and BCRP [5]. The distribution, expression quantities and spatial location of these efflux transporters are different in the human intestines. Intestinal efflux transporters are critical factors affecting oral absorption of drugs because these transporters can recognize, bind and excrete certain drugs into the intestinal lumen. Therefore, inhibiting the activity of intestinal membrane efflux transporters has gradually become a research hotspot to improve drug oral absorption [6][7]. It has been widely reported that many amphiphilic pharmaceutical excipients, such as D-a-tocopheryl polyethylene glycol 1000 succinate [6], Ployethylene glycols [8] and Pluronic [9], and small molecule compounds known as inhibitors positively suppress the activity of intestinal efflux transporters. The application of these excipients or inhibitors to prepare oral drug carriers can significantly improve oral drug absorption by reducing the intestinal drug efflux [10][11]. In addition, many novel nano-preparations including liposomes [12], microemulsions [13], solid lipid nanoparticles [7], and micelles [14], have significantly improved drugs oral absorption by inhibiting the activity of intestinal efflux transporters.

2. Intestinal Efflux Transporters

Small intestines of the human body are the main place for the absorption of nutrients and oral drugs. ATP-binding cassette (ABC) transporters are a class of membrane efflux transporters modulating the transport of drugs, exogenous and endogenous substances. Seven subfamilies (A-G) of ABC transporters have been found. Several different types of ABC membrane transporters distribute in intestinal epithelial cells, and these transporters could affect substances absorption by transporting substrates from enterocytes to intestinal lumen or blood in an ATP-dependent manner. Three efflux transporters of the ABC membrane proteins have been found on the lumen side of enterocytes, including P-gp [15], MRP2 [16] and BCRP [17], which function as an intestinal barrier due to them pumping drugs to intestinal lumen. MRP1-5 (other than MRP2) are on the basolateral side of enterocytes and actively transport oral substances from intestinal epithelial cells into the blood. Details of intestinal efflux transporters affecting substances absorption are described as follows.

2.1. P-gp

P-gp translated by ABCB1 gene (MDR1 gene) is one of ABC transporters in humans and rodents and widely distributes in the whole intestines [18]. The expression of P-gp in the intestines gradually increases from the duodenum to the colon and chiefly in the colon and distal small intestine [19]. Several nutrients and xenobiotics affect the expression of intestinal efflux transporters. The intestinal expression of P-gp obviously increased after rats received a fiber meal [20]. A wide variety of drugs such as paclitaxel, docetaxel, doxorubicin, and digoxin are not orally bioavailable due to intestinal P-gp pumps extruding these drugs from enterocytes to intestinal tract. To solve this problem, plenty of inhibitors (inhibiting P-gp activity or decreasing P-gp expression) such as verapamil, flavonoids, alkaloids, elacridar, tariquidar and zosuquidar, can be co-delivered with P-gp substrates to improve drug oral absorption by decreasing drugs efflux. More typical substances identified by P-gp or inhibiting P-gp activity are listed in Table 1.

2.2. MRPs

MRPs, the C subfamily of ABC transporters family, contain 9 proteins (MRP1-9), among which only MRP1-5 are related to the membrane transport of substances and have been reported to exist in intestine and colon of human [21]. Due to MRP2 special locality and relatively large expression quantities, it becomes one of the main intestinal efflux transporters that pumps certain substrates into the intestinal lumen. Intestinal MRP2 is to protect the organism from toxicants but it also affects some drugs absorption. It has been found that MRP2 is mainly expressed in the duodenum and jejunum, which may be related to its function [22]. Multiple factors modulate the expression of intestinal MRP2. Fructose-induced metabolic syndrome decreased intestinal MRP2 activity and expression, which could be reversed by geraniol and vitamin C [23]. The substrates of MRP2 include metabolites of endogenous and exogenous substances and organic anion compounds. More substrates and inhibitors of MRP2 are summarized in Table 1.

2.3. BCRP

BCRP is the second member of the G subfamily of ABC superfamily (ABCG2). Some substances can be pumped from enterocytes into the intestinal lumen by ABCG2. Therefore, ABCG2 can protect organisms from xenobiotics but it also reduces the oral absorption of drugs [24]. Studies have shown that BCRP extensively distributes in human intestines and its distribution is mainly concentrated in jejunal epithelial cells. Representative substrates and inhibitors of ABCG2 are summarized in Table 1. Researchers have found that some substrates (CYT387, Gefitinib, sorafenib etc.) of ABCG2 are also substrates of P-gp or MRP2 [24].
Table 1. Substrates and inhibitors of three main intestinal efflux transporters.
Transporters Substrates Inhibitors Refs.
P-gp digoxin, rhodamine-123, verapamil, rapamycin, cimetidine, silybin, atenolol, citalopram, mitoxantrone, doxorubicin, fexofenadine, rhodamine 123, aliskiren, betrixaban, celiprolol, paclitaxel and vincristine. verapamil, cyclosporine A, elacridar, tariquidar, zosuquidar, alkaloids, flavonoids, pyrimidine aminobenzene derivatives, 4-indolyl quinazoline derivatives, quercetin, ivermectin, Royleanone, HM30181A, thilphenylbenzofuran derivatives, encequidar, CBT-1®. [14][25][26][27][28][29][30][31][32][33][34][35][36]
MRP2 Valsartan, pravastatin, cisplatin, silybin, doxorubicin, sulfobromophthalein, dinitrophenyl-s-glutathione, calcein, methotrexate, ezetimibe glucuronide, resveratrol, etoposide, statins, and fexofenadine. MK571, indomethacin, cyclosporin A, Nomegestrol acetate sulfated metabolites, indomethacin, ivermectin. [31][37][38][39][40][41][42][43][44][45][46][47]
ABCG2 5-FU, silybin, zidovudine, cimetidine, nilotinib, bisantrene, ciprofloxacin, resveratrol, doxorubicin, mitoxantrone and topotecan. pyrimidine aminobenzene derivatives, reserpine, Ko143, reserpine, ivermectin. [38][41][43][44][45][48][49][50][51]

3. Excipients to Inhibit Efflux Transporters Activity

3.1. TPGS

D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a functional amphiphilic derivative of vitamin E and it can inhibit P-gp activity. In addition, TPGS is also an excellent agent that increases solubility of drugs and improves nano-formulations stability. The proven specific mechanisms of TPGS inhibiting P-gp include decreasing P-gp expressional amount, reducing mitochondrial membrane potential, depleting ATP and inhibiting P-gp-ATPase activity [52][53][54][55]. Owing to its P-gp inhibiting effect, amphiphilicity and degradability, TPGS has been widely used to prepare multiple nano-formulations to improve drug oral availability. Curcumin-loaded TPGS functionalized mesoporous nanocarriers outstandingly improved Curcumin oral bioavailability due to their small size and P-gp inhibition [6]. A nanocomplex composed of N-trimethyl chitosan and TPGS-modified poly (lactic-co-glycolic acid) was successfully prepared [56]. The oral bioavailability of the gemcitabine-loaded nanocomplex was 5.1 times higher than that of free gemcitabine due to P-gp inhibition. Microemulsion with TPGS as a surfactant was applied to deliver celecoxib, and the absorption of celecoxib greatly increased [57]. TPGS modified Daidzin-loaded zein nanoparticles were orally administrated to mice, and then the area under the curve (AUC) of the nanoparticles was wider and taller than that of Daidzin solution due to P-gp inhibition [58]. Oral PTX-loaded folate-conjugated Pluronic F127/polylactic acid polymersome modified by TPGS (PTX-loaded FA-F127-PLA/TPGS) were fabricated via a dialysis method. The AUC0–48h of PTX-loaded FA-F127-PLA/TPGS polymersome was 3737.14 ± 631.58 (ng/mL), while the AUC0–48h of Taxol® was 559.18 ± 113.90 (ng/mL) [59].

3.2. β-Cyclodextrin

β-Cyclodextrin (β-CD), a common polysaccharide, is usually used as a pharmaceutical ingredient and it has a hydrophilic outside and a lipophilic inside hole where hydrophobic drugs can be implanted [60][61]. In addition to improving drugs solubility, β-CD also inhibits P-gp by weakening P-gp-ATPase activity [62]. β-CD derivatives including Methyl-β-CD and Heptakis-β-CD have excellent inhibitory effect on P-gp activity [63]. In addition, β-CD also affects the activity of the drug metabolic enzyme CYP3A. Therefore, nanocarriers composed of β-CD and its derivatives have obtained more attention owning to them inhibiting P-gp activity and increasing drugs solubility. The Tacrolimus (KF506)-loaded hydroxypropyl-β-CD complexes were freeze-dried to form copolymer powders nanoparticles and its intestinal permeability value Papp significantly increased in inverted gut sac model, which was mainly due to these nanoparticles inhibiting P-gp activity [64]. Caco-2 cells were co-treated with R8-CM-β-CD (a derivatives of β-CD) and rhodamine-123 (a P-gp substrate), and then the internalized rhodamine-123 increased by 128%, which indicated that R8-CM-β-CD might have the ability of inhibit P-gp activity [65]. Insulin was loaded into R8-CM-β-CD to prepare a supramolecular complex (insulin/ R8-CM-β-CD) that showed excellent intestinal absorption, which might be attributed to that insulin/R8-CM-β-CD inhibited P-gp activity and improved intestinal insulin permeability [65]. The efflux ratio of nintedanib (a P-gp substrate)-loaded SEB-β-CD (a β-CD derivative) complex was 6–8 times lower than that of free nintedanib solution, which might be attributed to SEB-β-CD complex increasing nintedanib solubility and reducing P-gp activity [66]. Owning to it inhibiting P-gp activity and increasing solubility of drugs, β-CD is an ideal functional excipient improving drugs oral absorption.

3.3. Pluronic

Pluronic is an amphiphilic excipient that composes of a central hydrophobic chain with two hydrophilic chains attached by the side, and it usually function as stabilizer and surfactant. More importantly, it has been found that Pluronic copolymers could modulate efflux transporters activity [67]. P-gp activity can be inhibited by many types of Pluronic such as Pluronic 85, Pluronic F127, Pluronic F-68, Pluronic L92 and Pluronic L61 [4][68][69][70]. Pluronic F127-grafted-chitosan (Pl-g-CH), a polymeric derivative of Pluronic F127, obviously increased intracellular fluorescence intensity of rhodamine-123, which proved that Pluronic F127 inhibited P-gp activity while the specific mechanisms of how to inhibit P-gp were not further studied [71]. Compared to digoxin (a P-gp substrate) alone, the intracellular amounts of digoxin in LLC-PK1-P-gp cells treated with digoxin and Pluronic 85/tween 80 obviously increased, indicating that Pluronic 85/tween 80 inhibited P-gp-mediated digoxin efflux [68]. As an efflux transporters inhibitor and amphiphilic agent, Pluronic has been applied to prepare various nano-formulations to improve drugs oral absorption. Baicalein-loaded Pluronic P85/F68 micelles (B-MCs) were employed to reverse MRP2-mediated efflux of baicalein (a MRP2 substrate) [72].

3.4. PEGs

The molecular weights of Ployethylene glycols (PEGs) change from 200 to 35,000. In addition to improving drugs solubility, PEGs (PEG-400/PEG-2000/PEG-20000) were also found to inhibit P-gp-mediated-rhodamine-123 efflux in a concentration depended on manner while the concrete mechanisms of how PEGs affected P-gp function were not researched [73]. In the existence of PEG-400, the permeable ability of ganciclovir (a P-gp substrate) was obviously increased, which indicated that PEG-400 suppressed P-gp activity [70]. After fresh rat intestinal mucosa was treated with PEG-grafted polyethyleneimine (PEI) thiolated by γ-thibutyrolatone (PEG-g-PEI) co-polymer and Rhodamin-123, the accumulative absorption of Rhodamine-123 greatly increased compared to Rhodamine-123 alone, indicating that PEG-g-PEI co-polymer might be a novel material inhibiting P-gp function [74]. In general, PEGs and its derivatives serving as functional materials inhibiting P-gp are important for improving drugs oral absorption.

4.5. Others

In addition to the mentioned excipients, Tween 20, Brij 58, Tween 80, sodium carboxymethyl cellulose and Cremophor EL, explicitly inhibited P-gp efflux function in MDCK-MDR1 cells in a concentration-depended manner [8]. It was also found that Tween 20, Brij 30 and Cremophor EL inhibited P-gp and ABCG2 activity [75]. Docusate sodium, sodium lauryl sulfate and sucrose monolaurate obviously blocked the ABCG2 efflux activity [76]. Polysorbate 20 had an excellent inhibiting effect on P-gp [77][78]. As efflux transporters inhibitors and solubilizer, these materials can be used to prepare liposomes, micelles, nanoparticles and self-microemulsions to improve oral availability of drugs. It is necessary to find more amphiphilic excipients with the function of inhibiting intestinal efflux transporters activity, which would help researchers to better overcome intestinal drugs efflux. The well proven mechanisms of different excipients improving drug oral bioavailability are clearly concluded in Table 2.
Table 2. Excipients to enhance oral drug bioavailability.
Materials Mechanism of Improving Oral Drug Bioavailability Refs.
TPGS Inhibiting P-gp and increasing solubility of insoluble drugs. [52][53][54][55]
PEGs Inhibiting drugs efflux mediated by P-gp. [70]
β-CD Reducing P-gp activity and improving solubility of insoluble drugs. [60][61][63]
Pluronic Inhibiting the activity of MRP2 and P-gp. [71][72][79]
Polysorbate 20 Inhibiting P-gp activity. [77][78]
Tween 20 Inhibiting drugs efflux mediated ABCG2 and P-gp. [75]
Tween 80 Inhibiting P-gp activity. [8]
Docusate sodium, sodium lauryl sulfate and sucrose monolaurate Increasing the absorption of ABCG2 substrates. [76]
Cremophor EL Inhibiting ABCG2 and P-gp activities. [75]
Brij 30/58 Reducing activities of P-gp and ABCG2. [8][75]

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14061131

References

  1. Sims, K.R.; Yuan, L. Enhanced design and formulation of nanoparticles for anti-biofilm drug delivery. Nanoscale 2019, 11, 219–236.
  2. Okagu, O.D.; Verma, O. Utilization of insect proteins to formulate nutraceutical delivery systems: Encapsulation and release of curcumin using mealworm protein-chitosan nano-complexes. Int. J. Biol. Macromol. 2020, 151, 333–343.
  3. Wang, X.; Qiu, L.Z. Evaluation of intestinal permeation enhancement with carboxymethyl chitosan-rhein polymeric micelles for oral delivery of paclitaxel. Int. J. Pharm. 2020, 573, 118840.
  4. Negi, L.M.; Tariq, M. Nano scale self-emulsifying oil based carrier system for improved oral bioavailability of camptothecin derivative by P-Glycoprotein modulation. Colloids Surf. 2013, 111, 346–353.
  5. Dominguez, C.J.; Tocchetti, G.N. Acute regulation of apical ABC transporters in the gut. Potential influence on drug bioavailability. Pharmacol. Res. 2021, 163, 105251.
  6. Xie, J.; Yong, Y. Therapeutic Nanoparticles Based on Curcumin and Bamboo Charcoal Nanoparticles for Chemo-Photothermal Synergistic Treatment of Cancer and Radioprotection of Normal Cells. ACS Appl. Mater. Interfaces 2017, 9, 14281–14291.
  7. Ji, H.; Tang, J.L. Curcumin-loaded solid lipid nanoparticles with Brij78 and TPGS improved in vivo oral bioavailability and in situ intestinal absorption of curcumin. Drug Deliv. 2016, 23, 459–470.
  8. Gurjar, R.; Chan, C.Y.S. Inhibitory Effects of Commonly Used Excipients on P-Glycoprotein in Vitro. Mol. Pharm. 2018, 15, 4835–4842.
  9. Patil, S.; Choudhary, B. Enhanced oral bioavailability and anticancer activity of novel curcumin loaded mixed micelles in human lung cancer cells. Phytomedicine 2015, 22, 1103–1111.
  10. Mu, Y.; Fu, Y.M. Multifunctional quercetin conjugated chitosan nano-micelles with P-gp inhibition and permeation enhancement of anticancer drug. Carbohydr. Polym. 2019, 203, 10–18.
  11. Fang, J.; Zhang, S.W. Quercetin and doxorubicin co-delivery using mesoporous silica nanoparticles enhance the efficacy of gastric carcinoma chemotherapy. Int. J. Nanomed. 2018, 13, 5113–5126.
  12. Li, Y.; Arranz, E. Mucus interactions with liposomes encapsulating bioactives: Interfacial tensiometry and cellular uptake on Caco-2 and cocultures of Caco-2/HT29-MTX. Food Res. Int. 2017, 92, 128–137.
  13. Qu, D.; Wang, L.X. Oral Nanomedicine Based on Multicomponent Microemulsions for Drug-Resistant Breast Cancer Treatment. Biomacromolecules 2017, 18, 1268–1280.
  14. Qu, G.; Hou, S.Y. Self-assembled micelles based on N-octyl-N’-phthalyl-O-phosphoryl chitosan derivative as an effective oral carrier of paclitaxel. Carbohydr. Polym. 2019, 207, 428–439.
  15. Silva, R.; Vinia-Boas, V. Modulation of P-glycoprotein efflux pump: Induction and activation as a therapeutic strategy. Pharmacol. Ther. 2015, 149, 1–123.
  16. Yu, F.; Zhang, T.P. The Circadian Clock Gene Bmal1 Controls Intestinal Exporter MRP2 and Drug Disposition. Theranostics 2019, 9, 2754–2767.
  17. Hira, D.; Terada, T. BCRP/ABCG2 and high-alert medications: Biochemical, pharmacokinetic, pharmacogenetic, and clinical implications. Biochem. Pharmacol. 2018, 147, 201–210.
  18. Sajid, A.; Lusvarghi, S. Reversing the direction of drug transport mediated by the human multidrug transporter P-glycoprotein. Proc. Natl. Acad. Sci. USA 2020, 117, 29609–29617.
  19. Yano, K.; Tomono, T. Ogihara, Advances in Studies of P-Glycoprotein and Its Expression Regulators. Biol. Pharm. Bull. 2018, 41, 11–19.
  20. Mai, Y.; Gavins, F.K.H. A Non-Nutritive Feeding Intervention Alters the Expression of Efflux Transporters in the Gastrointestinal Tract. Pharmaceutics 2021, 13, 1789.
  21. Drozdzik, M.; Busch, D. Protein Abundance of Clinically Relevant Drug Transporters in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens. Clin. Pharmacol. Ther. 2019, 105, 1204–1212.
  22. Dietrich, C.G.; Geier, A. ABC of oral bioavailability: Transporters as gatekeepers in the gut. Gut 2003, 52, 1788–1795.
  23. Zecchinati, F.; Barranco, M.M. Reversion of down-regulation of intestinal multidrug resistance-associated protein 2 in fructose-fed rats by geraniol and vitamin C: Potential role of inflammatory response and oxidative stress. J. Nutr. Biochem. 2019, 68, 7–15.
  24. Durmus, S.; Hendrikx, J.J. Apical ABC transporters and cancer chemotherapeutic drug disposition. Adv. Cancer Res. 2015, 125, 1–41.
  25. Yin, T.; Zhang, Y. The efficiency and mechanism of N-octyl-O, N-carboxymethyl chitosan-based micelles to enhance the oral absorption of silybin. Int. J. Pharm. 2018, 536, 231–240.
  26. Semeniuk, M.; Mottino, A.D. Regulation of hepatic P-gp expression and activity by genistein in rats. Arch. Toxicol. 2020, 94, 1625–1635.
  27. Al-Saraf, A.; Holm, R. Tween 20 increases intestinal transport of doxorubicin in vitro but not in vivo. Int. J. Pharm. 2016, 498, 66–69.
  28. Nielsen, R.B.; Kahnt, A. Montmorillonite-surfactant hybrid particles for modulating intestinal P-glycoprotein-mediated transport. Int. J. Pharm. 2019, 571, 118696.
  29. Mai, Y.; Ashiru-Oredope, D.A.I. Boosting drug bioavailability in men but not women through the action of an excipient. Int. J. Pharm. 2020, 587, 119678.
  30. Saaby, L.; Helms, H.C. IPEC-J2 MDR1, a Novel High-Resistance Cell Line with Functional Expression of Human P-glycoprotein (ABCB1) for Drug Screening Studies. Mol. Pharm. 2016, 13, 640–652.
  31. Jin, S.; Wang, X.T. P-glycoprotein and multidrug resistance-associated protein 2 are oppositely altered in brain of rats with thioacetamide-induced acute liver failure. Liver Int. 2013, 33, 274–282.
  32. Yuan, S.; Wang, B. Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors. J. Med. Chem. 2021, 64, 14895–14911.
  33. Joshi, P.; Vishwakarma, R.A. Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer. Eur. J. Med. Chem. 2017, 138, 273–292.
  34. Sajid, A.; Raju, N. Synthesis and Characterization of Bodipy-FL-Cyclosporine A as a Substrate for Multidrug Resistance-Linked P-Glycoprotein (ABCB1). Drug Metab. Dispos. 2019, 47, 1013–1023.
  35. Cui, J.; Liu, X. Chow, Flavonoids as P-gp Inhibitors: A Systematic Review of SARs. Curr. Med. Chem. 2019, 26, 4799–4831.
  36. Lee, K.W.; Lee, K.H. Phase I/II Study of Weekly Oraxol for the Second-Line Treatment of Patients With Metastatic or Recurrent Gastric Cancer. Oncologist 2015, 20, 896–897.
  37. Arnold, Y.E.; Kalia, Y.N. Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early-Stage Drug Development. Biomedicines 2020, 8, 340.
  38. Yuan, Z.W.; Li, Y.Z. Role of tangeretin as a potential bioavailability enhancer for silybin: Pharmacokinetic and pharmacological studies. Pharmacol. Res. 2018, 128, 153–166.
  39. Huang, J.; Guo, L. Interactions between Emodin and Efflux Transporters on Rat Enterocyte by a Validated Ussing Chamber Technique. Front. Pharmacol. 2018, 9, 646.
  40. Ali, I.; Slizgi, J.R. Transporter-Mediated Alterations in Patients with NASH Increase Systemic and Hepatic Exposure to an OATP and MRP2 Substrate. Clin. Pharmacol. Ther. 2017, 104, 748–756.
  41. Rigalli, J.P.; Reichel, M. Human papilloma virus (HPV) 18 proteins E6 and E7 up-regulate ABC transporters in oropharyngeal carcinoma. Involvement of the nonsense-mediated decay (NMD) pathway. Cancer Lett. 2018, 428, 69–76.
  42. Di Giacomo, S.; Briz, O. Chemosensitization of hepatocellular carcinoma cells to sorafenib by beta-caryophyllene oxide-induced inhibition of ABC export pumps. Arch. Toxicol. 2019, 93, 623–634.
  43. Rigalli, J.P.; Scholz, P.N. The phytoestrogens daidzein and equol inhibit the drug transporter BCRP/ABCG2 in breast cancer cells: Potential chemosensitizing effect. Eur. J. Nutr. 2019, 58, 139–150.
  44. Rendic, S.P. Metabolism and interactions of Ivermectin with human cytochrome P450 enzymes and drug transporters, possible adverse and toxic effects. Arch. Toxicol. 2021, 95, 1535–1546.
  45. Yang, H.; Zhai, B.T. Intestinal absorption mechanisms of araloside A in situ single-pass intestinal perfusion and in vitro Caco-2 cell model. Biomed. Pharmacother. 2018, 106, 1563–1569.
  46. Nielsen, S.; Westerhoff, A.M. MRP2-mediated transport of etoposide in MDCKII MRP2 cells is unaffected by commonly used non-ionic surfactants. Int. J. Pharm. 2019, 565, 306–315.
  47. Tocchetti, G.N.; Zecchinati, F. Inhibition of multidrug resistance-associated protein 2 (MRP2) activity by the contraceptive nomegestrol acetate in HepG2 and Caco-2 cells. Eur. J. Pharm. Sci. 2018, 122, 205–213.
  48. Yu, Q.; Ni, D.C. Structures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism. Nat. Commun. 2021, 12, 4376.
  49. Ashar, Y.V.; Zhou, J.C. BMS-599626, a Highly Selective Pan-HER Kinase Inhibitor, Antagonizes ABCG2-Mediated Drug Resistance. Cancers 2020, 12, 2502.
  50. Jiang, H.; Yu, J. Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Regulate the Disposition of Acacetin Glucuronides. Pharm. Res. 2017, 34, 1402–1415.
  51. Hernandez-Lozano, I.; Wanek, T. Influence of ABC transporters on the excretion of ciprofloxacin assessed with PET imaging in mice. Eur. J. Pharm. Sci. 2021, 163, 105854.
  52. Gao, H.; Bai, Y. Self-Assembly Nanoparticles for Overcoming Multidrug Resistance and Imaging-Guided Chemo-Photothermal Synergistic Cancer Therapy. Int. J. Nanomed. 2020, 15, 809–819.
  53. Tian, G.; Zheng, X.P. TPGS-stabilized NaYbF4: Er upconversion nanoparticles for dual-modal fluorescent/CT imaging and anticancer drug delivery to overcome multi-drug resistance. Biomaterials 2015, 40, 107–116.
  54. Zhang, J.; Zhao, X.F. Systematic evaluation of multifunctional paclitaxel-loaded polymeric mixed micelles as a potential anticancer remedy to overcome multidrug resistance. Acta Biomater. 2017, 50, 381–395.
  55. Wempe, M.F.; Wright, C. Inhibiting efflux with novel non-ionic surfactants: Rational design based on vitamin E TPGS. Int. J. Pharm. 2009, 370, 93–102.
  56. Chen, G.; Svirskis, D. N-trimethyl chitosan coated nano-complexes enhance the oral bioavailability and chemotherapeutic effects of gemcitabine. Carbohydr. Polym. 2021, 273, 118592.
  57. Subongkot, T. Development and mechanistic study of a microemulsion containing vitamin E TPGS for the enhancement of oral absorption of celecoxib. Int. J. Nanomed. 2019, 14, 3087–3102.
  58. Zou, T.; Gu, L. TPGS emulsified zein nanoparticles enhanced oral bioavailability of daidzin: In vitro characteristics and in vivo performance. Mol. Pharm. 2013, 10, 2062–2070.
  59. Pan, X.Q.; Gong, Y.C. Folate-conjugated pluronic/polylactic acid polymersomes for oral delivery of paclitaxel. Int. J. Biol. Macromol. 2019, 139, 377–386.
  60. Li, X.; Uehara, S. Improvement of intestinal absorption of curcumin by cyclodextrins and the mechanisms underlying absorption enhancement. Int. J. Pharm. 2018, 535, 340–349.
  61. Yang, Y.; Liu, Y. Carboxymethyl beta-cyclodextrin grafted carboxymethyl chitosan hydrogel-based microparticles for oral insulin delivery. Carbohydr. Polym. 2020, 246, 116617.
  62. Zhang, Y.; Cui, Y.L. Effects of beta-cyclodextrin on the intestinal absorption of berberine hydrochloride, a P-glycoprotein substrate. Int. J. Biol. Macromol. 2013, 59, 363–371.
  63. Sosnik, A. Reversal of multidrug resistance by the inhibition of ATP-binding cassette pumps employing “Generally Recognized As Safe” (GRAS) nanopharmaceuticals: A review. Adv. Drug Deliv. Rev. 2013, 65, 1828–1851.
  64. Zhang, D.; Pan, X.L. Multifunctional Poly(methyl vinyl ether-co-maleic anhydride)-graft-hydroxypropyl-beta-cyclodextrin Amphiphilic Copolymer as an Oral High-Performance Delivery Carrier of Tacrolimus. Mol. Pharm. 2015, 12, 2337–2351.
  65. Yang, L.; Li, M.A. A cell-penetrating peptide conjugated carboxymethyl-beta-cyclodextrin to improve intestinal absorption of insulin. Int. J. Biol. Macromol. 2018, 111, 685–695.
  66. Vaidya, B.; Shukla, S.K. Nintedanib-cyclodextrin complex to improve bio-activity and intestinal permeability. Carbohydr. Polym. 2019, 204, 68–77.
  67. Batrakova, E.V.; Kabanov, A.V. Pluronic block copolymers: Evolution of drug delivery concept from inert nanocarriers to biological response modifiers. J. Control. Release 2008, 130, 98–106.
  68. Kwon, M.; Lim, D.Y. Enhanced Intestinal Absorption and Pharmacokinetic Modulation of Berberine and Its Metabolites through the Inhibition of P-Glycoprotein and Intestinal Metabolism in Rats Using a Berberine Mixed Micelle Formulation. Pharmaceutics 2020, 12, 882.
  69. Li, Y.; Chen, Z. The construction and characterization of hybrid paclitaxel-in-micelle-in-liposome systems for enhanced oral drug delivery. Colloids Surf. B Biointerfaces 2017, 160, 572–580.
  70. Li, M.; Si, L.Q. Excipients enhance intestinal absorption of ganciclovir by P-gp inhibition: Assessed in vitro by everted gut sac and in situ by improved intestinal perfusion. Int. J. Pharm. 2011, 403, 37–45.
  71. Sharma, S.; Verma, A. Investigating the role of Pluronic-g-Cationic polyelectrolyte as functional stabilizer for nanocrystals: Impact on Paclitaxel oral bioavailability and tumor growth. Acta Biomater. 2015, 26, 169–183.
  72. Chen, T.; Li, Y. Pluronic P85/F68 Micelles of Baicalein Could Interfere with Mitochondria to Overcome MRP2-Mediated Efflux and Offer Improved Anti-Parkinsonian Activity. Mol. Pharm. 2017, 14, 3331–3342.
  73. Shen, Q.; Lin, Y.L. Modulation of intestinal P-glycoprotein function by polyethylene glycols and their derivatives by in vitro transport and in situ absorption studies. Int. J. Pharm. 2006, 313, 49–56.
  74. Iqbal, J.; Hombach, J.L. Design and in vitro evaluation of a novel polymeric P-glycoprotein (P-gp) inhibitor. J. Control. Release 2010, 147, 62–69.
  75. Yamagata, T.; Kusuhara, H. Effect of excipients on breast cancer resistance protein substrate uptake activity. J. Control. Release 2007, 124, 1–5.
  76. Zou, L.; Pottel, J. Interactions of Oral Molecular Excipients with Breast Cancer Resistance Protein, BCRP. Mol. Pharm. 2020, 17, 748–756.
  77. Al-Ali, A.A.A.; Quach, J.R.C. Polysorbate 20 alters the oral bioavailability of etoposide in wild type and mdr1a deficient Sprague-Dawley rats. Int. J. Pharm. 2018, 543, 352–360.
  78. Nielsen, C.U.; Abdulhussein, A.A. Polysorbate 20 increases oral absorption of digoxin in wild-type Sprague Dawley rats, but not in mdr1a (-/-) Sprague Dawley rats. Int. J. Pharm. 2016, 513, 78–87.
  79. Batrakova, E.V.; Li, S. Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion. Br. J. Cancer 2001, 85, 1987–1997.
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