The effects of dietary and herbal phytochemicals on drug transporters

ADR-13061; No of Pages 18 Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr

The effects of dietary and herbal phytochemicals on drug transporters☆

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Yan Li a,b, Jezrael Revalde c, James W. Paxton c,⁎

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Article history: Received 4 April 2016 Received in revised form 10 August 2016 Accepted 5 September 2016 Available online xxxx

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Chemical compounds studied in this article: Curcumin (PubChem CID: 969516) Chrysin (PubChem CID: 5281607) Digoxin (PubChem CID: 2724385) Metformin (PubChem CID: 4091) (−)-Epigallocatechin gallate (PubChem CID: 65064) Talinolol (PubChem CID: 68770) SN-38 (PubChem CID: 104842) Quinine (PubChem CID: 3034034) Quercetin (PubChem CID: 5280343) Morin (PubChem CID: 5281670)

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Introduction . . . . . . . . . . . . . . . . . . . . . . . Absorption from gastrointestinal (GI) tract . . . . . . . . . 2.1. ABC transporters . . . . . . . . . . . . . . . . . 2.1.1. Pgp . . . . . . . . . . . . . . . . . . . 2.1.2. BCRP . . . . . . . . . . . . . . . . . . 2.1.3. Coordinated function of efflux and metabolism 2.2. SLC transporters . . . . . . . . . . . . . . . . . 2.2.1. OATP2B1 and OATP1A2 . . . . . . . . . . 2.2.2. Proton-coupled peptide transporters (PEPTs) 2.2.3. OCT family (OCT 1 and 2, SLC22A) . . . . . Hepatobilliary excretion . . . . . . . . . . . . . . . . . 3.1. SLC transporters . . . . . . . . . . . . . . . . . 3.1.1. OCT1 . . . . . . . . . . . . . . . . . .

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Contents

Membrane transporter proteins (the ABC transporters and SLC transporters) play pivotal roles in drug absorption and disposition, and thus determine their efficacy and safety. Accumulating evidence suggests that the expression and activity of these transporters may be modulated by various phytochemicals (PCs) found in diets rich in plants and herbs. PC absorption and disposition are also subject to the function of membrane transporter and drug metabolizing enzymes. PC–drug interactions may involve multiple major drug transporters (and metabolizing enzymes) in the body, leading to alterations in the pharmacokinetics of substrate drugs, and thus their efficacy and toxicity. This review summarizes the reported in vitro and in vivo interactions between common dietary PCs and the major drug transporters. The oral absorption, distribution into pharmacological sanctuaries and excretion of substrate drugs and PCs are considered, along with their possible interactions with the ABC and SLC transporters which influence these processes. © 2016 Published by Elsevier B.V.

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Keywords: ABC transporter SLC transporter Pharmacokinetics Food–drug interactions Phytochemical

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School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand School of Interdisciplinary Health Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand Department of Pharmacology & Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

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☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug Transporters: Molecular Mechanisms”. ⁎ Corresponding author. E-mail address: [email protected] (J.W. Paxton).

http://dx.doi.org/10.1016/j.addr.2016.09.004 0169-409X/© 2016 Published by Elsevier B.V.

Please cite this article as: Y. Li, et al., The effects of dietary and herbal phytochemicals on drug transporters, Adv. Drug Deliv. Rev. (2016), http:// dx.doi.org/10.1016/j.addr.2016.09.004

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2. Absorption from gastrointestinal (GI) tract Oral drug administration is regarded as the most convenient and safe route for drug delivery. In order for drugs to exert their beneficial effects (other than on the GI tract itself), they must be delivered to their target organ(s) and tissues by the systemic circulation. Adequate concentrations at the site(s) of action are only achieved by overcoming several absorption and metabolism barriers, both in the GI tract and in the liver (Fig. 1).

Foods/phytochemicals

Interaction with hepatic transporters can affect hepatic uptake and biliary excretion of drugs Interaction with renal transporters can affect drug excretion

Interaction withbloodbrain barrier transporters can affect drug distribution into brain

Interaction with intestinal transporters can affect drug absorption and bioavailability

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There is accumulating evidence that membrane transporter proteins play pivotal roles in drug absorption and disposition and thus determine the efficacy and safety of drugs [1–7]. Two major transporter superfamilies, namely the ATP-binding cassette (ABC) and the solute carrier (SLC) transporters, have been identified in the human genome. The human ABC transporter family contains 49 members with 7 subfamilies, including several important drug transporters, such as Pgp (ABCB1), MRP1-9 (ABCC1-6 and ABCC10-12, respectively) and BCRP (ABCG2) [2,8]. They actively efflux chemically diverse substrates, including amino acids, peptides, proteins, lipids, saccharides, inorganic ions, metals, and xenobiotics from cells. In most examples, transport of the substrates against their concentration and chemical-potential gradients is driven by the hydrolysis of ATP [9]. The SLC transporters include more than 300 influx transporters responsible for nutrient intake and drug disposition into important organs [10]. Both ABC and SLC transporters are present in all tissues and appear to play a fundamental role in defending the body against various exogenous toxins and carcinogens, as well as maintaining physiological homeostasis. The oral bioavailability and pharmacokinetic profile of each drug may be very different due to their great structural diversity. Consequently, the bioavailability and the distribution of these drugs at their site(s) of action in the tissue, are key factors that need to be established in association with their biological effects. Recently, various in vivo studies have demonstrated that drug transporters may determine drug disposition in various tissue and therefore efficacy and/or side effects. These transporters appear to be under tight transcriptional regulation by nuclear receptors, suggesting their functions are subject to dietary and environmental influences [2,5,11,12]. The expression and function of these transporters may be modulated by various phytochemicals (PCs) found in diets rich in plants and herbs [13–15]. PCs are most often associated with health benefits, with epidemiological and nutritional studies suggesting a protective role in the prevention of diabetes, cancer, cardiovascular and neurodegenerative diseases [16–25]. They include glucosinolates, organic isothiocyanates, dibenzocyclo-octadienes, sulfur-containing compounds of alliaceae, terpenoids (carotenoids, monoterpenes, and phytosterols), flavonoids and polyphenols (e.g., anthocyanins, flavones, flavan-3-ols, isoflavones, stilbenoids, catechin, epigallocatechin and ellagic acid) [16, 17]. The involvement of the ATP-binding cassette (ABC) and solute carrier (SLC) transporters in the pharmacokinetics of some drugs, and their

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implications in potential diet/herb-drug clinical interactions, will be 126 explored in this review. 127

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3.1.2. OATP1B1 and OATP1B3 . . . . . . . . . . . 3.1.3. Multidrug and toxin extrusion (MATE) proteins 3.2. ABC transporters . . . . . . . . . . . . . . . . . . . 3.2.1. Pgp . . . . . . . . . . . . . . . . . . . . 3.2.2. MRP2 . . . . . . . . . . . . . . . . . . . 3.2.3. BCRP . . . . . . . . . . . . . . . . . . . . 3.2.4. MRP1 and 3 . . . . . . . . . . . . . . . . . 4. Blood–brain barrier . . . . . . . . . . . . . . . . . . . . . 4.1. SLC transporters . . . . . . . . . . . . . . . . . . . 4.2. ABC transporters . . . . . . . . . . . . . . . . . . . 4.2.1. Pgp . . . . . . . . . . . . . . . . . . . . 4.2.2. BCRP . . . . . . . . . . . . . . . . . . . . 5. Renal excretion . . . . . . . . . . . . . . . . . . . . . . 5.1. SLC transporters . . . . . . . . . . . . . . . . . . . 5.1.1. OAT1 and 3 . . . . . . . . . . . . . . . . . 5.1.2. OCT2 . . . . . . . . . . . . . . . . . . . . 5.2. Multidrug and toxin extrusion (MATE) proteins . . . . 5.3. ABC transporters . . . . . . . . . . . . . . . . . . . 5.3.1. Pgp . . . . . . . . . . . . . . . . . . . . 5.3.2. BCRP and MRP2 . . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Y. Li et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

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Fig. 1. Effect of phytochemicals on absorption and disposition of drugs in humans.

Please cite this article as: Y. Li, et al., The effects of dietary and herbal phytochemicals on drug transporters, Adv. Drug Deliv. Rev. (2016), http:// dx.doi.org/10.1016/j.addr.2016.09.004

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The human family of ABC transporters contains 49 members with 7 subfamilies, including several important xenobiotic transporters, such as Pgp (ABCB1), MRP1-9 (ABCC1-6 and ABCC10-12, respectively) and BCRP (ABCG2) [2,8]. They actively efflux chemically diverse substrates, including amino acids, peptides, proteins, lipids, saccharides, inorganic ions, metals, and xenobiotics from cells. In most examples, transport

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2.1.1. Pgp Pgp, encoded by the multidrug resistance gene (ABCB1), is a 170-kDa protein with 1280 residues in a single polypeptide [35,36]. The protein can be split into two homologous halves, each half composed of one trans-membrane domain with 6 trans-membrane α-helices and one cytoplasmic nucleotide binding domain linked by a cytoplasmic 60 amino acid linker chain. It is an efflux transporter located on the plasma membrane in many tissues such as intestine, liver, kidney and brain. Pgp transports various structurally and pharmacologically diverse drugs, including vinca alkaloids (vinblastine, vinorelbine) [37], camptothecin derivates (topotecan) [38], tubulin polymerizing drugs (paclitaxel, docetaxel), anthracyclines (doxorubicin, idarubicin) [39], epipodophyllotoxins (etoposide) [40], tyrosine kinase inhibitors (e.g., erlotinib and imatinib), antibiotics (e.g., grepafloxacin) [41], anticonvulsants (e.g., dabigatran, rivaroxaban, and apixaban) [42], antihypertensives (e.g., nicardipine and talinolol) [43,44], digitalis glycosides (e.g., digoxin) [45], immunosuppressive agents (e.g., cyclosporine) [46], anticoagulants (e.g., ximelagatran) [47], steroids (e.g., cortisol, aldosterone, and dexamethasone) and HIV protease inhibitors (e.g., saquinavir, ritonavir, and nelfinavir) [48]. Typical synthesized inhibitors of Pgp include verapamil, cyclosporine A, tamoxifen, quinidine, erythromycin, elacridar (GF120918), zosuquidar (LY335979) and tariquidar (XR9576) [26,48–51]. Pgp is exclusively localized on apical (AP) side of intestine tissue and effluxes substrate drugs into the gut lumen and limits drug entry and contributes to intestinal drug excretion [52–54]. It can limit the bioavailability of substrates, although some drugs with high intrinsic permeability and solubility may circumvent the barrier function of intestinal Pgp [55–57]. Pgp concentrations vary considerably over the length of the GI tract, with ABCB1 mRNA and Pgp protein expression gradually increasing from the duodenum to the ileum and colon [58,59]. Since most marketed oral drugs are absorbed from the duodenum, this also extended the complexity of Pgp functionality. Nevertheless, the important roles of intestinal Pgp in absorption of its substrates have been confirmed in vivo by comparing the pharmacokinetics between: 1) wildtype and Abcb1a/1b (−/−) mice; and 2) human subjects with or without co-administration of Pgp inhibitors [54,60].

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of the substrates against their concentration and chemical potential 172 gradients is driven by the hydrolysis of ATP [9]. 173

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Aqueous solubility is recognized as a key factor for the bioaccessibility and thus bioavailability of many drugs. Once dissolved into GI fluids, a drug is usually absorbed across the GI wall, following the basic rule of thumb that “the more lipophilic, the more efficient is the absorption”, provided that it is not subject to transporter-mediated absorption. Atypical absorption kinetics of many drugs (which cannot be predicted from their physicochemical properties) can be caused by interactions with intestinal ABC and SLC transporters. Transporter-related absorption phenomena, such as limited or nonlinear intestinal permeability and absorption of drugs, may result in extensive variability in their oral bioavailability, resulting in inadequate plasma concentrations and lack of pharmacological effect on the one hand, or elevated concentrations and toxicity on the other. Many ABC and SLC transporters have been identified in the GI tract, including the organic anion transporting polypeptide 1A2 (OATP1A2, SLCO1A2) and 2B1 (OATP2B1, SLCO2B1), oligopeptide transporter PEPT1 (SLC15A1), P-glycoprotein (Pgp, ABCB1), multidrug resistance protein 2 (MRP2, ABCC2) and breast cancer resistance protein (BCRP, ABCG2) on the apical membrane, and organic cation transporter 1 (OCT1, SLC22A1) and MRP3, 4, 5 (ABCC3, 4 and 5) on the basolateral (blood) side (Fig. 2) [2,8,26–34]. Most PCs consumed in our diet, or taken as supplements or herbal medicines, are present in GI tract at relatively abundant concentrations. Many PCs have been reported to act as substrates/inhibitors/modulators of the ABC transporters, such as Pgp, BCRP and MRP2 (Table 1), which can severely limit the oral bioavailability of co-administered drugs. To date, the important SLC transporters involved in xenobiotic absorption and disposition mainly include the OATP family and proton-coupled peptide transporters (Fig. 2).

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3

ATP

MRP 3

K+ ATP

MRP 4

ATP

ATP

MRP 5

OCT2

Na+

Basolateral side Fig. 2. Localization of important ABC and SLC transporters in human small intestine.

Please cite this article as: Y. Li, et al., The effects of dietary and herbal phytochemicals on drug transporters, Adv. Drug Deliv. Rev. (2016), http:// dx.doi.org/10.1016/j.addr.2016.09.004

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Y. Li et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

Table 1 An overview of tissue distribution, PC substrates and inhibitors of Pgp, MRPs and BCRP (?, not determined, numbers inside brackets are IC50 values) Name Official Tissue location symbol

PC substrates

PC inhibitors

References

t1:4

Pgp

Quercetin, Narigenin, Biochanin A

[64–68,78,119–122]

t1:5

MRP1 ABCC1

All major tissues

ECG

t1:6

MRP2 ABCC2

Liver, kidney, intestine, brain

ECG 4-O-methyl-EGCG

t1:7

MRP3 ABCC3

Small intestine, pancreas, colon, placenta

Baicalein-7-glucuronide Resveratrol, resveratrol-3-glucuronide

Genistein, naringin, naringenin, hesperetin, acacetin, apigenin, chrysin, 6′,7′-epoxybergamottin, 6′,7′-dihydroxybergamottin, CBT-1, tetrandine, fangchinoline, quinine, curcumin, ECG, EGCG, CG, ginsenosides. Quercetin, Naringenin, Kaempferol,Apigenin, Genistein, Schisandrin A and B, Schisandrol A and B, Curcumin Myricetin (15.0 μM), Robinetin (22.2 μM) Curcumin (5 μM) ?

t1:8

MRP4 ABCC4

Kidney

?

t1:9

MRP5 ABCC5

Most tissues

?

t1:10

BCRP

Placenta, liver, the small intestine, colon, lung, kidney

Quercetin, genistein, resveratrol, resveratrol-3-glucuronide, resveratrol-3-sulfate, malvidin, petunidin, malvidin-3-galactoside, malvidin-3,5-diglucoside, cyanidin-3-galactoside, peonidin-3-glucoside and cyanidin-3-glucoside

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Quercetin, silymarin Quercetin, Silymarin Curcumin Curcumin, retusin, ayanin, genistein, naringenin, hesperetin, acacetin, apigenin, chrysin, chrysoeriol, laricitrin, myricetin, myricetin 3′,4′,5′-trimethylether, pinocembrin, quercitrin, tamarixetin, tricetin and tricetin 3′,4′,5′-trimethylether diosmetin, luteolin, galangin, kaempferide, kaempferol, erberine, celastrol, ellagic acid, limonin, oleanolic acid, propyl gallate, sinapic acid, ursolic acid, cyanidin, peonidin, cyaniding-3,5-diglucoside, malvidin, pelargonidin, delphinidin, petunidin, delphinidin-3-glucoside, cyaniding-3-rutinoside, malvidin-3-glucoside, pelargonidin-3,5-diglucoside, malvidin-3-galactoside, cannabinoids

[290–292] [236,293,294]

[147,293,294]

[293–295] [293–296] [102,117,126,297]

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R

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215 216

C

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Several flavonoids (quercetin, genistein, naringenin and hesperetin), which constitute major classes of PCs in most herbs and fruits, are inhibitors of Pgp (Table 1) and may significantly influence intestinal absorption of Pgp substrates. For example, the oral bioavailability of nonmetabolizable Pgp substrate fexofenadine was increased by 55% when coadministered with the Pgp inhibitor quercetin in humans [15]. Although quercetin also inhibits human BCRP and MRP2 [61,62], fexofenadine was not a substrate of either transporter based on a recent study using a zinc finger nuclease-mediated ABCG2/ABCC2 knock-out Caco-2 cell monolayer model [63]. Other potent Pgp inhibitors were also identified from several furanocoumarins (e.g., 6′,7′-epoxybergamottin and 6′,7′-dihydroxybergamottin) and some alkaloids (e.g., quinine, CBT-1® (a plant bisbenzylisoquinoline alkaloid), tetrandine and fangchinoline) [64–68]. Increased absorption of Pgp substrates has also been reported in patients having concomitantly taken foods and drinks rich in phytochemicals. Some of these recorded cases have been life-threatening as many of these drugs, such as the anticancer agents (e.g., irinotecan), cardiovascular agents (e.g., digoxin), and immunosuppressants (e.g., cyclosporine), have a narrow therapeutic index. For example, a lethal pharmacokinetic interaction between quercetin and digoxin was observed in pigs, which was thought to be due to enhanced digoxin absorption caused by inhibition of intestinal Pgp efflux by quercetin [69]. In addition, 1 μM epigallocatechin-3-gallate (EGCG, a major component of green tea) significantly inhibited Pgp mediated transport of digoxin in human Caco-2 monolayer. Commercial green tea may have EGCG concentrations up to 1 mM [70], implying that inhibition of intestinal Pgp by such a popular beverage could affect disposition of Pgp substrates and thus may cause side effects in humans. In addition, modulation of intestinal Pgp expression by PCs may change the pharmacokinetics of some drugs. For example, chronic use of St. John's wort can significantly induce intestinal Pgp resulting in markedly decreased absorption and bioavailability of digoxin [71,72], indinavir [73] and fexofenadine [74] in humans. For some new oral

N

211 212

U

210

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E

D

ABCG2

Liver, intestine, kidney brain

P

ABCB1

F

t1:3

anticoagulants (e.g., dabigatran, rivaroxaban and apixaban), coadministration of St. John's wort may cause decreased drug absorption and should be avoided [75]. Flavonoids, such as tangeritin, quercetin and naringenin, up-regulate ABCB1 gene expression due to their agonistic activity on the constitutive androstane receptor (CAR)- and pregnane X receptor (PXR)-mediated pathways [76,77], which leads to an increased Pgp protein and functional activity. In contrast, curcumin, derived from the spice turmeric, down-regulated ABCB1 gene expression in several human cancer cell lines over-expressing Pgp [78–80]. Interestingly oral dosed curcumin (60 mg/kg/day) for 4 consecutive days led to a down-regulation of the intestinal Pgp but an upregulation of hepatic Pgp levels, with no effect on renal Pgp in male Sprague–Dawley rats, indicating tissue-specific modulation [81]. The maximum plasma concentrations (Cmax) and area under the concentration–time curve (AUC(0–8h)) for oral celiprolol, administered on the fourth day at 30 mg/kg, were significantly raised by 1.9- and 1.6-fold, respectively. Piperine is another well-studied alkaloid (from black pepper) with evidence of Pgp inhibition [82,83]. Piperine inhibited Pgp-mediated digoxin and cyclosporine transport across Caco-2 cell monolayers and increased intestinal absorption of fexofenadine in rats [83,84]. In addition, piperine caused an increase in Pgp protein and ABCB1 mRNA levels after incubation of Caco-2 cells for 48 and 72 h [83]. As with curcumin, in vivo administration of piperine to rats for 14 days resulted in an increase in intestinal Pgp concentrations but a decrease in the liver [85]. Given the complexity of PC/food/herb–drug interactions, these knowledge gaps have to be addressed to prevent undesirable and harmful clinical consequences.

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2.1.2. BCRP BCRP is a 72-kDa protein composed of 665 amino acids, which is encoded by the gene ABCG2. The highest expression of BCRP occurs in the placenta (the syncytiotrophoblasts), followed by brain capillaries, the small and large intestines, liver, lung, kidney, adrenal, mammary and sweat glands, and the endothelia of veins [86–88]. Consistent

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298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342

383

2.2.1. OATP2B1 and OATP1A2 Several uptake transporters, such as the OATPs from the SLC transporter superfamily are also functionally expressed on the apical side of human intestine tissues [5,149]. The latter have recently been reported to be involved in the oral absorption of some drugs, but there are very few studies on their interactions with PCs [5]. Recently OATP1A2 and OATP2B1 have been suggested to mediate intestinal absorption of several drugs and PCs [29,150,151]. The co-localization of these uptake and efflux transporters with their counteracting transport mechanisms makes it more difficult to predict the outcome of their PC/food–drug interactions. For example, a decreased bioavailability of celiprolol (by 87%), talinolol and fexofenadine in the presence of grapefruit juice (GFJ) has been observed in humans [152–155]. As celiprolol, talinolol and fexofenadine are substrates of both Pgp and OATP and undergo very little metabolism, it was concluded that the inhibition of intestinal OATP uptake, rather than Pgp efflux, was the major interaction between PCs and GFJ. To add to this complexity, compounds such as aliskiren (a renin inhibitor used to treat hypertension) may be a substrate for CYP3A4, Pgp and OATP2B1 (Km 72 μM) [156]. Co-administration of aliskiren with GFJ (a well-known source of various potent inhibitors of the aforementioned enzyme/transporters) decreased its oral absorption and bioavailability [157], and was explained by inhibition of OATP2B1-

384 385

O

F

2.2. SLC transporters

R O

296 297

P

294 295

343 344

D

292 293

2.1.3. Coordinated function of efflux and metabolism Accumulating evidence suggests that intestinal ABC transporters may function as barriers to absorption of drugs and PCs (e.g., resveratrol, green tea catechins and flavonoids) by cooperating with the array of phase I and II metabolic enzymes [56,129–136]. The cytochrome P450-dependent mixed-function oxidases (CYPs) 1A, 2C, 2D and 3A are subfamilies responsible for the phase I metabolism of the majority of oral drugs/PC [137]. CYP3A4 and Pgp are both present in the enterocytes and the latter increases CYP3A4-mediated intestinal metabolism of their dual substrates by controlling the “rate of presentation” of drugs to the intracellular enzyme [133–136]. Both CYP3A4 and Pgp share many of the same inducers and inhibitors. In vivo evidence has demonstrated that the oral bioavailability of these dual substrates (e.g., paclitaxel, docetaxel, cyclosporine) may be increased by concomitant administration of common PC inhibitors (e.g., quercetin and naringenin) [138–140]. The phase II conjugation reactions most often yield a more polar and water-soluble metabolite. The most common conjugation reaction for drugs/PCs usually involves the formation of a βglucuronide which is catalysed by a family of enzymes known as the uridine diphosphoglucuronosyl transferases (UGTs). Other less common conjugations with a sulfo moiety (SO − 3 ) or glutathione may also occur, catalysed by various sulfotransferases (SULTs) and glutathione-S-transferases (GSTs), respectively. Recently it has been suggested that intestinal ABC transporters may function as barriers to absorption of drugs (e.g., raloxifene, a selective estrogen receptor modulator; ezetimibe, a cholesterol absorption inhibitor) and PCs (e.g., resveratrol, green tea catechins and flavonoids) by cooperating with phase II metabolic enzymes [56,129–132,141, 142]. For example, the oral bioavailability of raloxifene, chrysin and resveratrol is severely limited by extensive intestinal phase II metabolism and active efflux of the Phase II metabolites back into the GI tract for faecal elimination [141,143–146]. BCRP and MRP2 play pivotal roles in effluxing the phase II conjugates into intestinal lumen [147,132]. Similarly, ezetimibe glucuronide is a high-affinity substrate of MRP2, while ezetimibe is transported by Pgp and MRP2. Up-regulation of intestinal Pgp, MRP2, and UGT1A1 by rifampin was associated with markedly decreased AUC for ezetimibe and its glucuronide and increased intestinal clearance, leading to nearly abolished sterol-lowering effects [148].

E

290 291

T

288 289

C

286 287

E

284 285

R

283

R

281 282

N C O

279 280

with its tissue localization, mounting evidence suggests that BCRP functions as an efflux pump limiting fetal exposure, brain penetration, intestinal absorption of substrate xenobiotics and facilitating their mammary, biliary and kidney secretion [88–100]. Drug substrates for which BCRP has the highest affinity include sulfasalazine, mitoxantrone, topotecan, daunorubicin, flavopiridol, prazosin, cladribine and rosuvastatin [26,101–104]. BCRP transports substrate drugs more efficiently at low pH, independent of the dissociation status of the substrate [105]. Several potent BCRP inhibitors that have been identified include the Pgp antagonist GF120918 (IC50, 50 nM) [106,107], a natural product fumitremorgin C (FTC) and its analogue Ko134 (both IC50 b 1 μM) [94,108] and several kinase inhibitors, such as gefitinib (IC50, 300 nM) and imatinib (IC50, 170 nM) [109,110]. The expression of ABCG2 transcripts is greatest in the duodenum and subsequently decreases in the direction of the colon [111]. To the best of our knowledge, there is no published data of the distribution of BCRP protein expression along the human GI tract. The ABCG2 mRNA level in human jejunum is higher than that of Pgp [27,112], indicating that BCRP plays an important role in limiting the intestinal absorption of its substrates. The oral bioavailability of topotecan was higher in patients heterozygous for the c.421CNA allele of ABCG2 gene than those with wild type alleles [113]. Compared to wild type mice, knocking out mouse Abcg2 led to significant increases (~ 5–111-fold) in the oral absorption and bioavailability of substrates, including sulfasalazine, daidzein, genistein, rosuvastatin and topotecan [89,96,114,115]. Although species differences in this transporter might limit the use of these knockout models in predicting the contribution of BCRP to drug bioavailability in humans, a more recent study using humanized BCRP (hBCRP) mice confirmed the important role of BCRP in oral absorption and bioavailability of typical drugs and PC substrates mentioned above [116]. Several flavonoids derived from fruit and herbs, such as quercetin, kaempferol, resveratrol and diverse anthocyanins and anthocyanidins (commonly found in grapes and berries), malvidin, petunidin, malvidin-3-galactoside, malvidin-3,5-diglucoside, cyanidin-3-galactoside, peonidin-3-glucoside and cyanidin-3-glucoside have also been identified as BCRP substrates [105,117,118]. There is accumulating evidence, mainly from in vitro studies, that many dietary and herbal PCs are potent Pgp and BCRP inhibitors. These include curcumin, retusin, ayanin, genistein, biochanin A, quercetin, morin, phloretin, silymarin (a mixture of silibinins, isosilyin A and B, silychristin A and B, and silydianin), chrysin, hesperetin, naringenin, epicatechin gallate (ECG), catechin gallate (CG) and EGCG (Table 1) [64,117,119–124]. It has been suggested that such inhibitory PCs could be used to reverse the ABC transporter-based constraints on the GI absorption of other substrate PCs/drugs and that this may represent a useful strategy for improving their bioavailability. For example, curcumin increased the bioavailability of a well-defined BCRP substrate sulfasalazine 3.2-fold at the therapeutic dose in healthy subjects [125]. Co-administration of curcumin also increased the intestinal absorption and bioavailability of sulfasalazine in wildtype but not in Abcg2(−/−) mice [13,125], suggesting that the effect was Bcrp-mediated. Two flavonoids, chrysin (IC50, 0.20 μM) and benzoflavone, potent BCRP/Bcrp inhibitors [126], have no significant effect on oral topotecan pharmacokinetics in rats or Abcb1a/1b (−/−) mice [127]. However, the oral absorption and apparent bioavailability of topotecan increased in the presence of GF120918, a dual BCRP/Pgp inhibitor, in humans and in Pgp-deficient mice [89,128]. To add to the complexity of these interactions, chrysin increased the Cmax and bioavailability of oral nitrofurantoin (a specific BCRP/Bcrp1 substrate) in rats by more than 1.7-fold [14]. The likely explanation of this increase in bioavailability, is Bcrp1 inhibition by chrysin rather than metabolism, as the contribution of CYP1A-mediated metabolism of nitrofurantoin was reported to be minor. From these examples, it is apparent that inhibition of intestinal BCRP might be substrate/inhibitor-dependent and also speciesdependent, thus warranting further evaluation in humans.

U

277 278

5

Please cite this article as: Y. Li, et al., The effects of dietary and herbal phytochemicals on drug transporters, Adv. Drug Deliv. Rev. (2016), http:// dx.doi.org/10.1016/j.addr.2016.09.004

345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382

386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406

6

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Y. Li et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

t2:1 t2:2 t2:3

Table 2 An overview of tissue distribution, PC substrates and modulators of OATPs, OATs, OCTs and MATEs (?, not determined; * substrate-dependent stimulator, numbers are Km values for substrates or IC50 values for inhibitors)

414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429

t2:4

Name

t2:5 t2:6

ECG, EGCG OATP1A2 SLCO1A2 Brain (BBB), (OATPA) Kidney, Cholangiocytes SLCO1B1 Liver ? OATP1B1 (OATP2; OATPC)

PC inhibitors

OATP1B3 (OATP8; LST-2)

SLCO1B3

Liver

ECG, EGCG

t2:11

OATP2B1 (OATPB)

SLCO2B1

Liver, brain (BBB), intestine, placenta, heart

?

t2:12

OAT1

SLC22A6

Kidney

t2:13

OAT3

SLC22A8

t2:14 t2:15

OCT1 OCT2

SLC22A1 SLC22A2

Kidney, brain (BBB and choroid plexus cells) Liver, intestine Kidney, intestine

t2:16

MATE1

SLC47A1

Liver, kidney

Quinine

t2:17

MATE2-K

SLC47A2

Kidney

Quinine

O

t2:9 t2:10

PC stimulator

References

Naringin, hesperidin, ECG, EGCG, apigenin, kaempferol, quercetin

?

[150,151,252,253,298]

Biochanin A, genistein, ursolic acid, oleanolic acid, 8-trans-p-coumaroyloxy-α-terpineol, quercetin 3-Ο-α-L-arabinopyranosyl (1→2) α-L-rhamnopyranoside, silymarin, silybin A silybin B, silychristin Quercetin 3-Ο-α-L-arabinopyranosyl (1→2) α-L-rhamnopyranoside, silymarin, silybin A silybin B, silychristin

Rutin

[150,191,204,215,299,300]

E

C

PC substrates

R

Tissue location

R

t2:7 t2:8

Official symbol

T

E

D

430 431

2.2.2. Proton-coupled peptide transporters (PEPTs) The oligopeptide transporter PEPT1 (SLC15A1) is mainly expressed at the apical membranes of intestinal epithelial [168] and is committed to intestinal absorption of various drugs, including β-lactam antibiotics (e.g., amino-penicillin and cephalosporins, such as cefaclor, cephalexin, cefadroxil, cefixime, ceftibuten, and cefdinir), antivirals (e.g., L-valylacyclovir, a prodrug of acyclovir), naturally occurring peptide JBP485, anti-bacterial agent alafosfalin, angiotensin converting enzyme inhibitors (e.g., captopril and enalapril), renin inhibitors, thrombin inhibitors, antitumor drugs (e.g., betastin, 5-aminolevulinic acid), anti-epileptic agent NP-647, anti-hypotensive midodrine, metabotropic glutamate Glu2/3 receptor agonist LY544344, and a dipeptidyl derivative of LDopa, L-Phe-Dopa [6,60]. A recent study showed resveratrol increased

O

413

R O

411 412

P

409 410

reported to strongly inhibit OATP2B1 and OATP1A2 [150]. Similarly, apigenin, kaempferol, and quercetin have been reported to efficiently inhibit OATP1A2 and OATP2B1 transport activity [151]. However, it has been suggested that the contribution of OATP1A2 to intestinal drug absorption may be very minor due to its extremely low/negligible expression in human intestinal tissues [162–165]. Consequently, dietary supplements containing large amounts of abovementioned PCs may have the potential to reduce the absorption/bioavailability of OATP2B1 drug substrates, such as imatinib [166], talinolol [167], levofloxacin, fexofenadine, statins and methotrexate [29]. Thus, modulation of intestinal OATP transport by PCs may be a novel mechanism for food/ herb–drug interactions in humans. Other PC substrates and modulators of the OATPs are listed in Table 2.

F

432 433

mediated intestinal uptake of aliskiren. This perhaps implies that intracellular binding sites of Pgp and CYP3A4 are less accessible to a co-inhibitor(s) compared with those of OATP2B1, probably resulting in “first contact first service” phenomenon. Similarly, GFJ inhibited intestinal absorption of another co-substrate, montelukast and decreased its systematic exposure, which may lead to poor antiasthmatic effects in the clinic [158]. OATP2B1 also transports the toxic metabolite of irinotecan, SN-38. Such transport is saturable and pH-dependent and is decreased in the presence of baicalin (a flavonoid) or fruit juices, such as apple juice and GFJ [159]. In vivo gastrointestinal toxicity of SN-38 is a major issue with irinotecan-based chemotherapy. In mice, SN-38-induced GI toxicity was prevented by co-ingestion with apple juice. Thus, OATP2B1 may contribute to the uptake of SN-38 by intestinal tissues, triggering gastrointestinal toxicity. Apart from the conventional inhibition of bacterial β-glucuronidase in the gut with antibiotics, inhibition of OATP2B1 may be a novel strategy to prevent gastrointestinal toxicity without disturbance of the normal intestinal microflora. Inhibition of OATP2B1 by apple juice or a mixture of phloridzin, phloretin, hesperidin, and quercetin at the concentrations present in apple juice appeared to be “irreversible” (i.e., “non-competitive”) and last for a relatively long period [160], suggesting that it may be helpful for the prophylaxis of late-onset diarrhea caused by irinotecan therapy. In addition, OATP2B1-mediated uptake of estrone-3-sulfate can be inhibited by the extracts of bilberry, echinacea, green tea, banaba, grape seed, ginkgo, and soybean in HEK293 cells stably expressing human OATP2B1 [161]. Green tea catechins, ECG and EGCG, have been

U

N

C

Kaempferol-3-glucoside, isorhamnetin-3-glucoside, catechin, EC, ECG, EGCG, kaempferol-3-rutinoside, quercetin-3-rhamnoside, quercetin-3-rutinoside, 6′,7′-dihydroxybergamottin, tangeretin, naringin, naringenin, nobiletin, silymarin, silybin A silybin B, silychristin Ellagic acid, morin (300 nM), luteolin Fisetin, (470 nM), silybin, fisetin, quercetin quercetin-3′-O-sulfate, quercetin-3′-O-sulfate, genistein-4′-O-sulfate genistein-4′-O-sulfate Daidzein-7-O-glucuronide, Morin, daidzein-7-O-glucuronide, genistein-7-O-glucuronide, genistein-7-O-glucuronide, glycitein-7-O-glucuronide, glycitein-7-O-glucuronide, quercetin-3′-O-glucuronide quercetin-3′-O-glucuronide Quinine Quinine, EGCG (14 μM) Quinine Quinine

Quinine (1.9 μM) EGCG Quinine (6.4 μM) EGCG

EGCG*, quercetin [150,199,202,215,300] 3-Ο-α-L-arabinopyranosyl (1→2) α-L-rhamnopyranoside* ? [28,161,254,300–304]

?

[272,276,280,305,306]

?

[279,280,307–309]

? Quercetin, rutin, naringenin, naringin, genistein, genistin, and xanthohumol ?

[173,184] [121,173,185]

?

[70,222]

[70,222]

Please cite this article as: Y. Li, et al., The effects of dietary and herbal phytochemicals on drug transporters, Adv. Drug Deliv. Rev. (2016), http:// dx.doi.org/10.1016/j.addr.2016.09.004

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Y. Li et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524

3.1. SLC transporters

532

OCT1, OAT2, OATP1B1 and OATP1B3 are located in the sinusoid membrane of the liver (Fig. 3), extracting xenobiotics from blood and have become recognized as important determinants of hepatic uptake and clearance of a wide variety of drugs [188].

533

O

F

531

527 528 529 530

534 535 536

3.1.1. OCT1 Human OCT1 is mainly expressed in the liver and responsible for the hepatic uptake of many cationic drugs. For example, OCT1 genotype is a determinant of hepatic uptake of metformin and thus its therapeutic effects [180,189]. OCT1 is a high-capacity transporter for sumatriptan, an anti-migraine triptan, with a Km of 55 μM and Vmax of 978 pmol/mg protein/min [190]. Hepatic uptake was not affected by the Met420del polymorphism, but was strongly reduced by Arg61Cys and Gly401Ser, and completely abolished by Gly465Arg and Cys88Arg, resulting in a doubling of plasma concentrations in humans with two deficient OCT1 alleles compared with those with fully active OCT1. Interestingly, several drugs (e.g., atropine, prazosin) are potent inhibitors of OCT1 but apparently, not substrates [4]. Similarly, EGCG and green tea inhibited OCT1 with an IC50 value for green tea of 1.4% (v/v, containing 14 μM EGCG) [70]. The unbound EGCG peak concentration is estimated to be at 5–10 μM in the portal vein after drinking green tea. Thus, EGCG might inhibit hepatic uptake of an OCT1 substrate (e.g., metformin, sumatriptan) and increase its plasma concentration in patients drinking green tea or taking herbal supplements containing a high dose of EGCG.

537 538

3.1.2. OATP1B1 and OATP1B3 OATP1B1 (LST1/OATPC/OATP-2/SLCO1B3) is a liver-specific transporter that mediates the uptake into the hepatocytes of a broad range of drugs, including statins (e.g., pravastatin [191], fluvastatin [192]), antibiotics (e.g., rifampicin [193], beta lactam antibiotics [194]), angiotension II receptor blockers (e.g., olmesartan [195], valsartan [196]), HIV protease inhibitors [197], fexofenadine [198], methotrexate [199] and SN-38 [200], as well as several endogenous substrates, such as bile salts, conjugated steroids, eicosanoids, thyroid hormones and coproporphyrins I and III [201,28,165,202–204]. Accumulating evidence suggests that genetic variants affecting OATP1B1 activity are important determinants of the hepatic clearance of its substrates [205–207]. For example, in subjects containing one non-synonymous mutations (c.521TN C), both the AUC of pravastatin and renal excretion were increased nearly two-fold compared to wild-type [208], suggesting that this single polymorphism may cause compromised OATP1B1 activity and thus diminished hepatic clearance of pravastatin. Similarly, SN-38 plasma exposure was significantly increased in 521TNC allele carriers treated with irinotecan [209–211]. Severe toxicities associated with increased SN-38 exposure have also been reported in a patient with 388AN G allele [212]. Similar to OATP1B1, OATP1B3 (LST2/OATP8/SLCO1B3) is predominantly expressed in human liver [199]. It shares with OATP1B1 many common substrates, such as statins (e.g., pravastatin, rosuvastatin), angiotension II receptor blockers (e.g., olmesartan, valsartan), rifampicin, bosentan, hormone conjugates, bile salts and thyroid hormones. Evidence has indicated that several drugs including paclitaxel, docetaxel, imatinib and telmisartan are substrates of OATP1B3, but not OATP1B1 [213,214].

556 557

R O

477 478

3. Hepatobilliary excretion

P

475 476

525 526

D

473 474

2.2.3. OCT family (OCT 1 and 2, SLC22A) Members of the OCT family (SLC22A1-3) are expressed in the human GI tract and play important roles in the disposition of organic cations. Initially OCT1 was detected on the basolateral (BL) side of human small intestinal epithelial cells by using a rat Oct1 antibody [171]. However, a recent study using a validated anti-human OCT1 antibody showed that it is exclusively expressed on the apical side of human/mouse small intestine and Caco-2 cell monolayer [172]. A short hairpin RNA-mediated SLC22A1 knockdown in Caco-2 cells decreased apical uptake of pentamidine (a specific OCT1 substrate) by ∼50%, but did not alter basolateral uptake. Similarly, chemical inhibition of OCT1/Oct1decreased apical but not basolateral uptake of pentamidine into human/mouse small intestine. Typical substrates of OCT1 include cationic drugs, such as metformin, cimetidine, imatinib and pentamidine, and non-drugs such as dopamine, prostaglandin E2, Nmethylquinine and 1-methyl-4-phenylpyridinium (MPP+) [173–178]. However, OCT1/Oct1 appears to have very limited effects on intestinal absorption of metformin based on pharmacogenetics studies in humans and in Slc22a1(−/−) mice [179,180]. The plasma membrane monoamine transporter (PMAT; SLC29) is abundantly expressed on the apical side of human intestinal tissues and has been suggested to be responsible for the intestinal absorption of metformin [181]. Based on an in vitro knock-down study, OCT1 and PMAT appeared to contribute to approximately 20% and 40%, respectively, of the apical uptake of metformin in a Caco-2 cell monolayer model [182]. In addition, type 2 diabetic patients with two reduced functioning OCT1 alleles who were treated with OCT1 inhibitors, were over four times more likely to develop GI intolerance [183]. Taken together, we postulate that intestinal OCT1 may mainly act as an apical efflux pump for metformin in vivo. Reduced intestinal OCT1 activities may increase metformin accumulation in intestine tissues, leading to GI intolerance. Green tea has recently been reported to inhibit OCT1-mediated metformin transport with IC50 values of 1.4% (v/v, containing 14 μM EGCG) [70]. A comparison of the transport activity in the presence of either 10% (v/v, containing 100 μM EGCG) green tea or 100 μM EGCG shows a higher inhibitory efficacy for green tea than for 100 μM EGCG, suggesting other components in green tea may act synergistically on OCT1. The estimated gut EGCG concentration is about 1 mM after drinking green tea and is sufficient to inhibit intestinal OCT1. This might increase risk of GI intolerance to metformin especially in patients with reduced functioning OCT1 alleles but further investigations are required. OCT2 is reported to be expressed on the basolateral side of human small intestinal epithelial cells, facilitating the permeation of organic cations across the cell membrane [171]. Green tea inhibited OCT2-mediated metformin transport with IC50 values of 7.0% (v/v, containing 70 μM EGCG). Quinine is a PC substrate for both OCT1 and 2, and may act as a competitive inhibitor of OCT1 or 2 [173,184,185]. In Caco-2 cell monolayers, basolateral uptake rate of cimetidine, a substrate of OCT2, was enhanced 145–295% when co-treated with flavonoids, such as quercetin, rutin, naringenin, naringin, genistein, genistin, and xanthohumol [121]. One possible mechanism involves the interaction of some flavonoids with a wide range of protein kinases, including protein kinase C (PKC), serine/threonine kinases, cAMP-dependent protein kinase and tyrosine

kinases [186]. Kinase Yes1 inhibition in vivo diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy [187]. We hypothesize that some flavonoids may be kinase activators and thus induce OCT2 phosphorylation leading to increased OCT2 function. The exact mechanisms of this “stimulated uptake” by specific flavonoids remain unknown and further studies are required.

E

472

T

471

C

469 470

E

467 468

R

466

R

464 465

N C O

462 463

intestinal permeability of bestatin via upregulation of PEPT1 in Caco-2 cells [169]. In addition, the Cmax and AUC of bestatin were significantly increased by 2.0- and 1.6-fold, respectively, in rats pretreated with resveratrol for two weeks compared with control. An inwardly directed proton gradient, which is maintained by intestinal sodium/proton ATPases, is utilized as the driving force for PEPT1-mediated uptake. Interestingly, selected flavonoids (quercetin, genistein, naringin, diosmin, acacetin, and chrysin) have been reported to stimulate apical Na+/H+-exchange and a concomitant increase in the driving force for PEPT1, leading to enhanced absorption of cefixime in Caco-2 cells [170]. This may be a possible new mechanism for drug–PC intestinal absorption interactions.

U

460 461

7

Please cite this article as: Y. Li, et al., The effects of dietary and herbal phytochemicals on drug transporters, Adv. Drug Deliv. Rev. (2016), http:// dx.doi.org/10.1016/j.addr.2016.09.004

539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555

558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584

8

Y. Li et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

Hepatocyte Pgp OATP2B1

ATP

ATP

OCT1 OATP1B1

BCRP

Bile

MRP2

MATE1

ATP

OATP1B3

F

MRP3

Hepatocyte

Blood

R O

O

Blood

Fig. 3. Localization of uptake and efflux transporter in hepatocytes.

585 586

t3:1 t3:2 t3:3

Table 3 Common phytochemical substrates and inhibitors of Pgp, MRPs, BCRP and OATPs (I, inhibitor; S, substrate; ×, not a substrate or inhibitor; ?, not determined. The numbers are either IC50 values or Ki values (with *) in μM)

595 596

D

E

T

593 594

C

591 592

E

589 590

t3:4

Phytochemicals

Pgp

BCRP

MRP1

t3:5

Apigenin

?

I (0.055)

I

t3:6 t3:7

Biochanin A Curcumin

I I

I I (1.04)

t3:8 t3:9 t3:10

Cyanidin Daidzein EGCG

I I I (99.0)

I S, I ?

t3:11 t3:12 t3:13 t3:14 t3:15

ECG Genistein Hesperetin Hesperidin Kaempferol

? I I I I

t3:16

Myricetin

I

t3:17

Narigenin

t3:18

R

587 588

implications of altered pharmacokinetics by quercetin remain unknown and may warrant further investigation. In addition to these mainly inhibitory interactions, there is also evidence that the flavonoid, rutin, may stimulate OATP1B1mediated [3 H]dehydroepiandrosterone sulfate (DHEAS) uptake [215]. In addition, EGCG from green tea and another flavonoid quercetin 3-Ο-α- L -arabinopyranosyl (1 → 2) α- L -rhamnopyranoside showed substrate-dependent stimulation of uptake by OATP1B3 [150,215]. For example, OATP1B3-mediated uptake of Fluo-3 was noncompetitively inhibited by EGCG; whereas uptake of estrone-3sulfate was strongly stimulated by EGCG at low substrate concentrations. A similar stimulation effect has been reported for OATP1B3-mediated pravastatin uptake into isogenic cells by

P

597

There is also evidence that some PCs, such as ursolic acid, oleanolic acid, and 8-trans-p-coumaroyloxy-α-terpineol (derived from Rollinia emarginata Schlecht, Annonaceae; a plant with an antiprotozoal properties) and some flavonoids (quercetin, apigenin, kaempferol, biochanin A and genistein) are potent inhibitors of OATP1B1 [215–217]. Quercetin, apigenin, kaempferol and hyperforin also inhibited OATP1B3 activity [213,217] (Table 3). Quercetin concentrations in the portal vein were estimated to be up to 110 μM after ingesting food or herbal supplements, which is about 10-fold higher than Ki for OATP1B1/1B3 [217]. In healthy male subjects, co-administration of quercetin (500 mg orally, once daily for 14 days) increased the pravastatin AUC0–10 h and the peak plasma drug concentration, prolonged its elimination half-life and decreased its apparent clearance [218]. At this stage, the clinical

MRP4

MRP5

OATP1A2

OATP 1B1

OATP 1B3

OATP 2B1

References

I

?

?

?

? ?

? ?

? I

I (20.8*) ? ?

[61,126,151,215,217,291]

? I (5) ? ? S

? ? ?

? ? ?

? ? ?

? ? S, I (18.8)

I (0.6*) I I (3.8) ? ? I

I

I I (15) ? I S

I (32.4*) ? ?

? ? I

[117] [61,116,291] [70,119,150,313]

? S, I I I I (0.086)

S I ? ? ?

S S I ? I

? ? ? ? ?

? ? ? ? I

? ? ? ? ?

[150,313] [61,116,215] [314] [314] [126,217] [314]

I (15.0) S

?

?

?

?

[235]

S, I

I (13.6) I

? I ? ? I (16.0*) ?

I ? I (67.6) I (1.92) I (21.3)

I (1.55) I

S, I (10.4) ? ? ? I (25.2) ?

?

?

I

?

I (49.2)

[61,217,295]

Naringin

I

I

?

?

?

?

?

I

I (81.6) I

I (4.63)

[61,167,295,314]

t3:19 t3:20 t3:21

Phloretin Phloridzin Quercetin

I I S, I

I ? S,I (0.21)

? S I

? S S, I

? ? ?

? ? I

? ? I

Resveratrol Silymarin

I I

S,I I

I I

? ?

S ?

I I

× I

I (1.31) I (23.2) I (9.47) (8.7*) S I (0.3)

[310,314] [314,315] [61,126,151,295]

t3:22 t3:23

? ? I (22.0) ? ?

O

C

N

R

MRP3

U

MRP2

? ? I (8.8*) S I (1.3)

? I (33.7) ? ? S, I (12.0) S ? ? ? I (24.4*) ? I (101.1) I (197.5) ? ? I (7.8*) S I (2.2)

[290,310,311] [13,78,236,242,296,312]

[105,147,295,316,317] [120,295,300,318]

Please cite this article as: Y. Li, et al., The effects of dietary and herbal phytochemicals on drug transporters, Adv. Drug Deliv. Rev. (2016), http:// dx.doi.org/10.1016/j.addr.2016.09.004

598 599 600 601 602 603 604 605 606 607 608 609 610

Y. Li et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

3.2. ABC transporters

638 639

The major ABC transporters, Pgp, MRP2 and BCRP are located in the canalicular membrane of the liver, effluxing compounds into the bile [5, 225]. Evidence has indicated that the inhibition or impairment of these hepatocyte transporters can increase the concentrations of their drug/ PC substrates in the bloodstream, and/or decrease their biliary excretion, leading to a more prolonged stay in the body.

640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671

T

633 634

C

631 632

E

629 630

3.2.1. Pgp Hepatic Pgp is mainly responsible for biliary excretion of lipophilic and cationic drugs. It was reported that the biliary excretion clearance of digoxin is reduced in mdr1a/1b knock-out mice compared with wildtype [226]. The biliary excretion of camptothecin was decreased in rats treated with Pgp inhibitors such as cyclosporin A, quercetin, naringin and naringenin, compared with controls [227]. On the other hand, regulation of hepatic Pgp by PCs may result in changes in hepatic clearance of some Pgp substrates. Oral dosed curcumin (60 mg/kg/day) for 4 consecutive days led to upregulation of hepatic Pgp levels but downregulation of the intestinal Pgp in male Sprague–Dawley rat with no effect on renal Pgp [81]. This increased absorption and bioavailability of celiprolol, a Pgp substrate with minor metabolism. Pgp may not be a rate-limiting factor for biliary excretion of celiprolol. On the other hand, male Wistar rats intragastrically administered with piperine at the equivalent daily human consumption dose of 112 μg/kg for 14 days exhibited induced intestinal Pgp levels concomitant with a downregulation of hepatic Pgp. However, the clinical importance of dietary regulation of liver Pgp remains unclear.

R

627 628

R

625 626

N C O

623 624

U

621 622

F

637

619 620

3.2.2. MRP2 MRP2 transport various drug substrates, including methotrexate, vinblastine, irinotecan and its toxic metabolite SN-38, pravastatin, ceftriaxone and ampicillin [60], fosinopril (an angiotensin-converting enzyme inhibitor) [228], fexofenadine [229], lopinavir [230] and oxaliplatin [231], as well as glucuronide and sulfate metabolites of drugs or PCs [232]. For example, the biliary excretion of SN-38 glucuronide, was significantly lower in Mrp2-deficient Eisai hyperbilirubinemic (EHBR) rats when compared with normal rats [233]. Since the major

672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694

3.2.3. BCRP BCRP plays a pivotal role in the biliary excretion of its drug substrates and the sulfate metabolites of PCs and drugs (i.e., the nonMrp2-mediated component). For example, the biliary excretion of nitrofurantoin, fluoroquinolones and pitavastatin was significantly lower in Abcg2-deficient mice compared to wild-type animals [99, 100,241]. Hepatobiliary excretion of unchanged topotecan was also substantially decreased in Pgp-deficient mice pretreated with GF120918, leading to higher systemic exposure [89]. We and other groups have demonstrated that curcumin is a very potent inhibitor for human BCRP with IC50 values of 20–2000 nM [13,126, 242]. However, although curcumin has a very low oral bioavailability as mentioned previously [237], there remains the possibility that sufficiently high concentrations are achieved in the liver to potentially inhibit hepatic BCRP. For example, the liver to plasma exposure ratio for curcumin was reported to be more than 40:1 in mice [243]. Such potential food–drug interactions with BCRP may decrease hepatobiliary excretion of its drug substrates while simultaneously increasing intestinal absorption (or decreasing intestinal secretion). This could potentially have serious consequences for substrate drugs, such as the anticancer agents (e.g., imatinib and topotecan) which have a narrow therapeutic index.

695

3.2.4. MRP1 and 3 In contrast to Pgp, BCRP and MRP2, MRP1 and 3 are located at the sinusoid membrane and are involved in transporting substrates back into the bloodstream, but are expressed at low levels under normal conditions [244]. Evidence has indicated that Mrp3-null mice have enhanced GI tract toxicity after diclofenac treatment [245]. A major reactive diclofenac metabolite, diclofenac acyl glucuronide (DCF-AG) that covalently binds to biologic targets, may contribute to these adverse GI reactions. Mrp3 plays an important role in DCF-AG disposition and it also transports baicalein-7-glucuronide, a phase II metabolite of baicalein, which is present in many herbal supplements. Thus coadministration of baicalein with diclofenac may compromise MRP3/ Mrp3-mediated efflux of DCF-AG. However, the clinical relevance of this putative PC-drug interaction remains to be revealed.

717

4. Blood–brain barrier

731

D

635 636

3.1.3. Multidrug and toxin extrusion (MATE) proteins Multidrug and toxin extrusion (MATE; SLC47A) proteins contain two members, MATE1 and MATE2-K. Hepatic MATE1 is a proton antiporter expressed in the liver canalicular membrane mediating the excretion of organic cations and zwitterions into bile [220,221]. Its substrates include the vitamin thiamine, cimetidine, metformin, guanidine, procainamide, the antiviral agents (e.g., acyclovir and ganciclovir) and the antibiotics (e.g., cephalexin and cephradine) as well as an endogenous substrate creatinine. Quinine is an MATE1 substrate and a potent inhibitor of MATE1 (IC50 value of 1.9 μM) [222]. Coadministration of quinine with the antiviral agent ritonavir (a MATE1 inhibitor) markedly increased systemic exposure and elimination halflife of quinine in healthy subjects [223]. Since quinine is a well-known CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor, inhibition of both CYP3A4 and MATE1 would explain such dramatic changes in quinine pharmacokinetics. A recent study has reported green tea (IC50, 4.9%) and EGCG inhibit MATE1-mediated transport of metformin in vitro [70]. The clinical implication of this discovery remains unclear. In vivo in Mate1(−/−) mice, the hepatic concentration of metformin was markedly higher than in Mate1(+/+) mice, leading to metformin-induced lactic acidosis [224].

617 618

O

616

R O

615

pathway for irinotecan elimination is by biliary excretion of glucuronide conjugates in humans and rodents, the pharmacokinetics of irinotecan may be susceptible to pathological conditions where MRP2 may be deficient, such as in cholestatic liver disease or in Dubin–Johnson Syndrome, or after MRP2 inhibition/induction [2,234]. Two PC inhibitors of MRP2, curcumin (IC50 5 μM) and myricetin (IC50 15 μM), are common constituents in herb supplements [235,236]. However the bioavailability of curcumin is very low with maximum plasma concentrations of 120 nM after 8 g orally per day in pancreatic cancer patients for 4 weeks [237]. Consequently, curcumin may have very limited effects on inhibition of hepatic MRP2. However, the chronic administration of PCs may result in the up-regulation of MRP2 via activation of the pregnane X receptor (PXR) or the aryl hydrocarbon receptor (AhR) in hepatocytes [81,85,238], leading to increased hepatobiliary excretion of drugs and thus a lower bioavailability. Genetic variations of MRP2 are an important predisposing factor for herbal-induced toxic liver injuries [239], suggesting compromised MRP2 activity may lead to decreased hepatobiliary excretion of PCs or their metabolites from the liver. The biliary excretion of glucuronide and sulfate conjugates of silymarin flavonolignans was reduced by approximately 96 and 78%, respectively, in Mrp2-deficient Wistar rats compared to wild type [240]. However, the effects of PC glucuronide and sulfate conjugates on liver MRP2 activity remain unknown in humans.

P

613 614

rosiglitazone (a thiazolidinedione antidiabetic drug), resulting in a 400% increase in pravastatin uptake compared to pravastatin alone [219]. Given the complexity of such food/drug interactions and the increased popularity of green tea and other herbal supplements, caution is advised when consumed with pharmacotherapy.

E

611 612

9

696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716

718 719 720 721 722 723 724 725 726 727 728 729 730

Endothelial cells that line the microvasculature of the central 732 nervous system (CNS) constitute the blood–brain barrier (BBB), 733

Please cite this article as: Y. Li, et al., The effects of dietary and herbal phytochemicals on drug transporters, Adv. Drug Deliv. Rev. (2016), http:// dx.doi.org/10.1016/j.addr.2016.09.004

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Y. Li et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

Pgp

OATP1A2

BCRP

Blood

MRP4

ATP

ATP

ATP

O

F

Endothelial

Tight junction

R O

OAT3

Brain

Fig. 4. Localization of ABC and SLC transporters in the human BBB.

742

751 752

Generally a drug must be highly lipid-soluble, or subject to uptake transport processes, to cross the BBB, and then gain access to the brain. OATP1A2 (SLCO1A2; SLC21A3) is highly expressed in the apical (blood) side of the human BBB [251–254] and may facilitate its PC substrates, such as ECG and EGCG, to penetrate into the brain [150]. OATP1A2 transports analgesic opioids (e.g., [D-penicillamine2,5]encephalin, deltorphin II) [252], antimigraine triptans (e.g., sumatriptan), levofloxacin and methotrexate [255]. Some PCs, including ECG, EGCG, apigenin, kaempferol, and quercetin are also potent inhibitors of OATP1A2 [150, 151], and thus their influence on brain exposure to OATP1A2 substrates requires more studies.

753

4.2. ABC transporters

754

The ABC transporters may represent a major rate-limiting factor in PC distribution or access to the brain. ABCB1, ABCG2, ABCC1, ABCC3, ABCC4 and ABCC5 genes have been detected in the BBB using qRT-PCR [256]. According to a recent quantitative proteomics study, the two most abundant ABC transporters in the human BBB are BCRP and Pgp [257]. Both Pgp and BCRP have been located at the apical membrane of brain capillary endothelial cells, along with MRP1 (Fig. 4) [256,258].

755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770

C

E

R

R

O

749 750

C

747 748

N

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U

743 744

4.2.2. BCRP Interestingly, the uptake of typical BCRP substrates, mitoxantrone and dehydroepiandrosterone sulfate, into the brain did not vary significantly between wild type and Bcrp knockout mice [266]. In contrast in the same knockout mouse model, significant increases in the brain concentrations of topotecan (3-fold), genistein (9-fold), daidzein (6-fold) and coumestrol (4-fold) have been reported [114,116]. Brain concentrations of topotecan were moderately, but statistically significantly increased by 1.7-fold after 60 min in Abcg2 knockout mice compared to hBCRP animals [116]. BCRP expression levels in the BBB were recently determined to be around 2-fold greater in humans than in mice [257], suggesting perhaps a more limited brain penetration of these BCRP substrates in humans. Manipulation of BBB BCRP may alter brain drug/PC exposure. In a rat hemisphere perfusion study, the brain accumulation of quercetin was dramatically increased by pretreatment with GF120918 (a Pgp and BCRP inhibitor), but not with PSC833 (a Pgp inhibitor) [267]. A study using the ex vivo rat BBB model indicated that curcumin at 50 nM inhibited BCRP activity and significantly increased the penetration of sulfasalazine across the BBB [13].To put this into perspective, curcumin plasma concentrations peaked at 120 nM in pancreatic cancer patients after long-term large oral dosing [237]. Thus clinical studies on PC–drug interaction at BBB may warrant further investigation.

789 790

P

4.1. SLC transporters

771

D

741

737 738

of Glycyrrhiza glabra (licorice)) into the cerebrum increased significantly by co-perfusion with Pgp or Mrp1 inhibitors [263]. Camptothecin (a substrate for Pgp and BCRP) passage across the rat BBB was increased by a Pgp inhibitor cyclosporine but not several potent PC inhibitors of Pgp and BCRP including quercetin, naringin and naringenin [227], possibly due to the poor bioavailability of these PCs. In addition, dietary constituents and nutraceuticals may regulate the ABC transporters by activating PXR, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) or aryl hydrocarbon receptor (AhR) at the BBB [250]. For example, rats dosed with sulforaphane (an Nrf2 ligand derived from broccoli) exhibit increased protein expression of Pgp, MRP2, and BCRP at BBB and reduced delivery to the brain of a Pgp substrate verapamil [264]. Hyperforin is a constituent of St. John's wort and it is also a human PXR but not mice PXR ligand. It increased Pgp expression and transport activity in brain capillaries isolated from transgenic mice expressing human PXR (hPXR), but had no effects on BBB Pgp in wild type mice [265]. These examples highlight the fact that we are still a long way from being able to exploit our knowledge of Pgp in the clinic.

T

739 740

selectively excluding circulating drugs and toxic agents from entering the neural parenchyma but allowing essential nutrients, hormones and some drugs into the brain [246–250]. This selectivity is attributed to specialized features unique to the BBB, including expression of tight intercellular junctions that markedly limit paracellular permeability, plus a unique expression of ABC and SLC transporters that determine the transcellular permeability of nutrients, drugs and PCs (Fig. 4).

735 736

E

734

4.2.1. Pgp There is evidence that Pgp efficiently restricts the entry of a wide variety of drugs into the brain [259–261]. It also limited CNS exposure to several PCs. For example, the brain level of cryptotanshinone (a major triterpenoid of the traditional Chinese herbal medicine, Danshen) was 15- and 2-fold higher in Abcb1a(−/−) and Abcc1(−/−) mice, respectively, compared to wild-type mice, suggesting Pgp and Mrp1 may play significant roles in the restriction of cryptotanshinone penetration across the BBB [262]. Likewise in a bilateral in situ brain perfusion model, the uptake of glabridin (a flavonoid and major active constituent

Please cite this article as: Y. Li, et al., The effects of dietary and herbal phytochemicals on drug transporters, Adv. Drug Deliv. Rev. (2016), http:// dx.doi.org/10.1016/j.addr.2016.09.004

772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788

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Y. Li et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

Brush border membrane

Basolateral membrane

MRP2

ATP

MATE1, MATE2-K

OAT1 H+

Pgp

OCT2

ATP

OAT3 BCRP

816 817

OCT2, OAT1 and 3 and OATP4C1 are expressed on the basolateral side of the proximal tubule cells (PTCs) of the kidney; whereas OAT4, Pgp, MRP2, MRP4 and BCRP are on the brush border membranes, and all are involved in transporting xenobiotics and endogenous compounds out of the blood into the urine [5,268–271] (Fig. 5).

818

5.1. SLC transporters

819

5.1.1. OAT1 and 3 OAT1 and 3 are both expressed on the basolateral side of renal proximal tubule cells and take up drugs from the blood into the proximal tubule cells [272]. OAT1 can affect many systemic biological pathways including the tricarboxylic acid (TCA) cycle, tryptophan and other amino acids, fatty acids, prostaglandins, cyclic nucleotides, odorants, polyamines, and vitamins [273]. OAT3 appears to be essential for the handling of phase I and phase II metabolites, dietary flavonoids and antioxidants [274]. OAT1 and 3 share some common drug substrates, including ACE inhibitors (e.g., captopril and quinapril), diuretics (e.g., bumetanide and furosemide), ceperosporins (e.g., ceftibuten and ceftizoxime), NSAIDs (e.g., indomethacin, salicylate, ketoprofen), adefovir, methotrexate, cimetidine and ranitidine [275]. Benzylpenicillin and farmotidine appeared to be only transported by OAT3. A recent study showed that morin and luteolin are potent OAT1 inhibitors, with IC50 values of b0.3 and 0.47 μM, respectively [276]. As the in vivo Cmax values of morin and luteolin are 10 and 30-fold higher than their IC50 values for OAT1 inhibition, the potent inhibitory effect of morin and luteolin on OAT1-mediated drug transport may also occur in vivo and lead to altered renal clearance and pharmacokinetics. The renal clearance of methotrexate was reduced by 42% in the presence of morin in the rat [277]. In the clinic, decreased methotrexate clearance due to OAT inhibition may be fatal as exemplified by the potentially life-threatening methotrexate/NSAID interaction [278]. Morin also inhibited OAT3-mediated kidney accumulation of imipenem, protecting against imipenem-induced nephrotoxicity in rabbits [279]. A more recent study also suggested that epicatechin and EGCG are effective inhibitors of mouse Oat3 [274]. Many PCs are excreted as conjugated metabolites by the kidney, and consequently, there exists the possibility of competitive inhibition of these transport processes with drugs whose major route of elimination is via the kidney. For example, the sulfated conjugates of flavonoids,

830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850

C

E

R

R

828 829

N C O

826 827

U

824 825

883

5.2. Multidrug and toxin extrusion (MATE) proteins

899

Both MATE1 and MATE2-K are localized in the apical membrane of human kidney proximal tubules functioning as the final excretion step of drugs/toxins into urine. MATE2-K shares with MATE1 some common substrates such as cimetidine, metformin, guanidine and procainamide, while the zwitterionic cephalexin and cephradine were revealed to be substrates of MATE1, but not of MATE2-K [221]. While the IC50 of green tea was 4.9% (v/v) for inhibition of MATE1-mediated metformin transport, the IC50 value for MATE2-K-mediated metformin transport could not be calculated [70]. In vitro 100 μM EGCG significantly inhibited MATE1- and MATE2-K-mediated metformin transport. Such an unbound EGCG concentration may not be achieved after oral ingestion of green tea or herbal supplements.

900 901

R O

D

813

E

5. Renal excretion

T

812

822 823

5.1.2. OCT2 In human kidney proximal tubules, OCT1 was not detected but OCT2 is abundantly expressed in all three segments and plays a pivotal role of basolateral uptake of quinine, cimetidine, ranitidine, metformin and platinum drugs [285]. A very recent study showed that jatrorrhizine and epiberberine (alkaloids found in Chinese herbal medicines) are potent inhibitors of OCT2 with IC50 values of 2.3 μM and 3.1 μM, respectively [286]. After a single oral dose in rats, Cmax of jatrorrhizine and epiberberine were 5- and 8.5-fold higher than their IC50 values for OCT2, respectively. This suggests that these alkaloids may cause in vivo inhibition of renal excretion of OCT2 substrates such as metformin. Increased metformin concentration may cause life threatening risks of lactic acidosis especially in dehydrated patients or in patients with diabetic nephropathy [287]. Thus, it may be advisable that these patients avoid herbal medicines containing jatrorrhizine and epiberberine alkaloids.

P

Fig. 5. Schematic diagram of the drug transporters in the human kidney proximal tubules.

820 821

851 852

O

ATP

Proximal tubule epithelium

814 815

such as quercetin-3′-O-sulfate and genistein-4′-O-sulfate, were efficiently taken up by OAT1 in kidney [280]. On the other hand, glucuronide conjugates including daidzein-7-O-glucuronide, genistein-7-Oglucuronide, glycitein-7-O-glucuronide and quercetin-3′-O-glucuronide appeared to be preferential substrates for kidney OAT3 (Table 2). In addition, quercetin-3′-O-sulfate effectively reduced the uptake and cytotoxicity of adefovir in OAT1-overexpressing HEK293 cells [280]. These flavonoid conjugates inhibit OAT1 and OAT3 activity at physiologically relevant concentrations [280]. Since uptake by OAT1 and 3 is a rate-limiting step in the renal secretion process of many drugs, interaction of flavonoids and their conjugates with OATs may be an important mechanism for food/herb–drug interactions via inhibition of renal uptake. In addition, the therapeutic efficacy and the toxicity of many drugs may depend on the expression of OATs. The regulation of OAT transport activity in response to various stimuli can occur at several levels such as transcription, translation, and post-translational modification [281]. Post-translational regulation is usually a quick response (minutes to hours) to variable intake of drugs, fluids, or meals, as well as metabolic activity. It modifies target proteins through biochemical reactions, including glycosylation, phosphorylation, ubiquitination, sulfation, methylation, acetylation, and hydroxylation. Okadaic acid is a potent protein phosphatase inhibitor derived from sea sponge. It downregulates mOat-mediated transport of para-aminohippuric acid by enhancing phosphorylation of mOat [282]. Similarly, enhanced hOAT1 ubiquitination may lead to increased hOAT1 degradation in the proteasome, decreased hOAT1 expression at the cell surface, and inhibited hOAT1 transport activity [283]. EGCG appears to act as a proteasome inhibitor [284]. It may therefore be of interest to investigate whether EGCG can interfere with the ubiquitination of OATs. This will help better understand OAT-mediated PC–drug interactions and may warrant further investigation.

F

OAT4

11

Please cite this article as: Y. Li, et al., The effects of dietary and herbal phytochemicals on drug transporters, Adv. Drug Deliv. Rev. (2016), http:// dx.doi.org/10.1016/j.addr.2016.09.004

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917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933

951

6. Conclusions

952

Due to their suggested health benefits, there is increased interest in the community on PC use as supplements or as components in herbal remedies. PCs are processed by the same absorption, distribution, metabolism and excretion (ADME) mechanisms as those used by drugs [289], and thus the potential for PC–drug interactions is apparent. However, it is very difficult to predict the possibility of clinically significant PC–drug interactions because of the lack of information on the pharmacokinetics and pharmacodynamics of most PCs. Nevertheless, the greatest PC concentrations occur in the intestines and there is accumulating clinical evidence that modulation of intestinal transporters by co-administered PCs may change oral drug absorption and bioavailability. This research has confirmed that the majority of PCs appear to be multi-targeting inhibitors/modulators of both the ABC and SLC transport proteins. Most research on the interaction of the PCs with the transporters has been undertaken in vitro and has shown that both stimulation/induction and inhibition of substrate transport may result, and that the outcome is often dependent on the specific PC investigated, its concentration, exposure time, cell line and substrate used. Thus to predict clinical outcomes from in vitro data, various factors should be considered including: the available concentration of the PC in the intestines; drug/PC regimen; the different transporter kinetics (e.g., high affinity and high capacity for ABC transporters but low affinity

948 949

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C

E

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R

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R

942 943

O

940 941

C

938 939

N

936 937

U

934 935

References

1008

T

950

5.3.2. BCRP and MRP2 BCRP is expressed on the apical membrane of the proximal tubule cells and is involved in the tubular secretion of drug/PC substrates, such as ciprofloxacin and grepafloxacin. The kidney/plasma ratios were increased 3.6- and 1.5-fold for ciprofloxacin and grepafloxacin, respectively, in Bcrp (−/−) mice compared with wild type mice [100]. Various flavonoids are extensively metabolized by the Phase II enzymes and generate their conjugated metabolites, which are taken up from the blood by OAT1 and 3. These hydrophilic conjugates are then believed to be pumped out of the kidney proximal tubular epithelium into the urine by BCRP and OAT4, and to a lesser extent by MRP2. This coupled active secretion of conjugated metabolites of PCs may ultimately accelerate elimination of PCs from the systemic circulation in humans. However, the interaction of flavonoids and their conjugates with kidney ABC transporters may alter the pharmacokinetics of their drug substrates. Given the substrate diversity of MRP2, BCRP, and OATs, it would appear cautionary to monitor plasma concentrations for drugs with a narrow therapeutic index in patients who are also consuming large amounts of PCs, perhaps as herbal medications or health supplements.

F

915 916

O

5.3.1. Pgp Pgp is expressed on the brush border membranes and is responsible for the renal excretion of its substrates such as digoxin. It is well known that drug interactions that diminish digoxin excretion by Pgp inhibitors (e.g., quinidine, verapamil, cyclosprin A), require digoxin dose adjustment to prevent any toxicity. The mechanisms of such possiblyfatal drug–drug interactions (DDIs) have been elucidated using renal tubular LLC-PK1 cells overexpressing Pgp [288]. Using the same model, quercetin, naringenin, genistein, and xanthohumol reduced Pgp-mediated transport of cimetidine [121], implying these PCs may diminish Pgp-mediated cimetidine secretion. Kidney Pgp is also subject to regulation by various PC constituents in food, herbal remedies and nutraceuticals. Rats dosed with 128 μg/kg of capsaicin showed downregulated Pgp levels in the liver and kidney, but no change in intestinal Pgp level [85]. Similarly, a study showed higher systemic exposure for per-oral digoxin in male Wistar rats co-administered with a single oral dose of capsaicin (10 or 30 mg/kg). Systemic clearance of the drug was also lower than in control group, possibly due to decreased renal secretion of digoxin by Pgp.

974 975

R O

913 914

and high capacity for PEPT1 and PMAT); the different driving forces (e.g., ATP for ABC transporters; protons for PEPT1 and PMAT); and their specific localization and activity. The PC–drug interaction data with intestinal transporters have provided a unique perspective to better understand the complexities of intestinal drug absorption. Thus, the modulation of the expression and function of intestinal transporters by PCs should always be considered in context with other factors influencing drug absorption, such as the particular drug/PC formulations, the intestinal solubility of the drugs/PCs, intestinal transit time, regional differences of luminal pH and interactions with intestinal metabolizing enzymes. In contrast to the gut, there is considerably less information on whether various PCs, or perhaps more importantly their metabolites, can modulate the activity/expression of drug transporters in the excretory organs, such as the liver and kidney. The modulation of liver or kidney transporters may influence a drug's systemic clearance and change its residence time in the body. However, it is often extremely difficult to ascertain from in vivo results whether the transporters are solely responsible for the change in pharmacokinetics, as many PCs (e.g., flavonoids) are also substrates/modulators of various CYPs and UGTs which are also involved in the elimination of many drugs. Transporters can be up- or down-regulated by activation of specific nuclear receptors or transcription factors, but information is sparse on the modulatory effects of the various PCs on the tissue-specific expression of drug transporters. An additional complexity is also often present with in vivo studies of supplements or herbal medicines which often contain a variety of different PCs which may have additive/synergistic or even antagonistic effects. Similarly, there is a lack of data of PC–transporter interactions at the BBB and other organ barriers, which may modulate the penetration of drugs into these pharmacological sanctuaries. Further in vitro and in vivo studies, both in animal models and humans, are necessary to answer these questions. Certainly, caution is particularly advised when taking supplements or herbal remedies concurrently with drugs which have a narrow therapeutic range.

P

5.3. ABC transporters

D

912

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