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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][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][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][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 | ® | . | ][53][54][55] | [63,64,65,66] | [14][25][26][ | ,26 | 27][] | ,27 | 28] | ,28 | [29][30][31[ | ,29 | 32] | ,30 | [33] | ,31 | [34] | ,32 | [ | ,33 | 35 | ,34 | ][36] | [14,25,35,36] |
| 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] | |||||||||||||||||||||||
| PEGs | Inhibiting drugs efflux mediated by P-gp. | [70] | [81] | [45][46][47] | [31,37 | 41] | ,38 | [ | ,39 | 42 | ,40 | ][43][44] | ,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. | ||||||||||||||||||||||||
| β-CD | Reducing P-gp activity and improving solubility of insoluble drugs. | [60][61][63] | [71,72,74] | [38][41][43][44][45][48][49][50][51] | [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][63,64,65,66]. 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][67]. 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][68]. 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][69]. 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][70].
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][71,72]. In addition to improving drugs solubility, β-CD also inhibits P-gp by weakening P-gp-ATPase activity [62][73]. β-CD derivatives including Methyl-β-CD and Heptakis-β-CD have excellent inhibitory effect on P-gp activity [63][74]. 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][75]. 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][76]. 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][76]. 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][77]. 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][78]. 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][4,79,80,81]. 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][82]. 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][79]. 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][83].
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][84]. 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][81]. 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][85]. 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][86]. Docusate sodium, sodium lauryl sulfate and sucrose monolaurate obviously blocked the ABCG2 efflux activity [76][87]. Polysorbate 20 had an excellent inhibiting effect on P-gp [77][78][88,89]. 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 | |
| Pluronic | Inhibiting the activity of MRP2 and P-gp. | [71][72][79] | [82,83,90] |
| Polysorbate 20 | Inhibiting P-gp activity. | [77][78] | [88,89] |
| Tween 20 | Inhibiting drugs efflux mediated ABCG2 and P-gp. | [75] | [86] |
| Tween 80 | Inhibiting P-gp activity. | [8] | |
| Docusate sodium, sodium lauryl sulfate and sucrose monolaurate | Increasing the absorption of ABCG2 substrates. | [76] | [87] |
| Cremophor EL | Inhibiting ABCG2 and P-gp activities. | [75] | [86] |
| Brij 30/58 | Reducing activities of P-gp and ABCG2. | [8][75] | [8,86] |
