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ScienceDirect Go with the flow — membrane transport in the gut Editorial overview David T Thwaites Current Opinion in Pharmacology 2013, 13:843–846 For a complete overview see the Issue Available online 19th October 2013 1471-4892/$ – see front matter, # 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.coph.2013.09.019

David T Thwaites Institute for Cell & Molecular Biosciences, Faculty of Medical Sciences, Framlington Place, Newcastle University, Newcastle upon Tyne NE2 4HH, UK e-mail: [email protected] David Thwaites is Professor of Epithelial Physiology at Newcastle University. His research interests are in understanding how mammalian membrane transporters operate by identifying the physiological function, molecular identity and substrate selectivity of nutrient and drug transporters in the gastrointestinal tract, kidney and in cancer tissues.

The primary function of the gastrointestinal tract is the assimilation of nutrients from diet. The final stages of digestion and almost all absorption take place in the small intestine and, to a lesser extent, the large intestine. Thus, the intestinal epithelium, the single layer of polarised, differentiated cells that lines the wall of the intestine, sits at the interface between the outside world and the internal environment of the human body. It is across this epithelial barrier that all essential nutrients, vitamins, electrolytes and fluid are absorbed. Many toxins and waste products can be secreted directly across the intestinal epithelium or excreted through the biliary route. The gastrointestinal tract is of great interest to the pharmacologist, and the pharmaceutical industry beyond, because most patients, if given the opportunity, would choose to take medication orally rather than have it delivered by any other route. In addition, many drugs and metabolites are lost from the body by active secretion from the intestine and liver. Thus, the intestinal epithelium is a major target for clinical intervention to improve bioavailability and modulate gut function. To allow net transport in either the absorptive or secretory direction, the polarised cells in the small intestine (enterocytes), large intestine (colonocytes) and liver (hepatocytes) express a distinct set of membrane transport proteins in their apical and basolateral membrane domains. Each epithelial cell type mediates net solute and ion movement through the coordinated activity of an array of membrane transport proteins (primary active transporters or pumps, secondary active cotransporters or antiporters, and channels). The series of 10 reviews in this edition of Current Opinion in Pharmacology have been written by leading experts in each respective field and focus on the function of membrane transporters in the gastrointestinal tract. These membrane transport proteins can be viewed as targets for pharmacologists for three reasons. Firstly, membrane transporters in the gut can directly transport drugs and metabolites, either in the absorptive or secretory direction. Thus, membrane transporters can be targeted to improve bioavailability of orally delivered drugs. Secondly, membrane transporters and channels can be targets per se for pharmacological intervention by selective inhibitors or enhancers, where such intervention may be required under certain pathophysiological conditions. Thirdly, membrane transport protein expression can be modulated either by upregulation or downregulation in pathophysiological situations where there is a requirement to either augment or reduce transport, respectively. The first article in this series, by Misaka, Mu¨ller and Fromm [1], highlights recent observations from clinical studies in humans regarding the function of the drug efflux pumps P-glycoprotein (ABCB1), breast cancer resistance

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Current Opinion in Pharmacology 2013, 13:843–846

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protein (BCRP, ABCG2) and multidrug resistance protein 2 (MRP2, ABCC2), in the gut. These drug efflux proteins function as important defence mechanisms by protecting the body from toxins but also secrete drugs and metabolites into the intestinal lumen. The article reviews recent observations that emphasise that these efflux pumps are important in drug transport as they limit bioavailability of drugs, are sites of drug–drug interaction, and are subject to both inhibition and induction, both of which will modify rates of drug transport [1]. The second article by Tang, Hendrikx, Beijnen and Schinkel [2], nicely complements that by Misaka et al. [1] but focuses on evidence from studies using genetically modified mice. Tang et al. [2] include information on both secretory and absorptive transporters highlighting the potential key roles in intestinal drug transport of the multidrug resistance proteins Mrp2, Mrp3 (Abcc3), and Mrp4 (Abcc4), the organic cation transporters Octn1 (slc22a4) and Octn2 (slc22a5), and the equilibrative nucleoside transporter Ent1 (slc29a1). A recent review by van Waterschoot and Schinkel [3] summarises information from genetically modified mice for the important roles of the ATP-binding cassette (ABC) transporter P-glycoprotein and the drug metabolising enzyme cytochrome P450 3A (CYP3A) in intestinal drug handling, and very nicely supplements those by Misaka et al. [1] and Tang et al. [2]. A key observation from the reviews described above is that expression and activity of the drug efflux pumps may be subject to modulation by factors from the gastrointestinal lumen. This theme is continued in the next three reviews. Tamai and Nakanishi [4] review recent findings with the organic anion transporting polypeptide OATP2B1 (SLCO2B1) which is expressed at the brush-border membrane of the human small intestine and is involved in absorption of drugs such as the anti-allergy drug fexofenadine. Evidence supports the presence, within OATP2B1, of either multiple binding pockets for distinct substrates or multiple binding sites within a single pocket. OATP2B1 function and expression are modulated by common components of fruit juices (e.g. flavonoids) demonstrating that OATP2B1 in the intestine is a site not only for drug– drug but also drug-food/beverage interactions. Wenzel [5] continues this theme and describes recent investigations into the roles of dietary flavonoids in the control of both absorptive and secretory transporters in the small intestine. Evidence is available to support roles for dietary flavonoids in control of both glucose absorption and homeostasis, and drug efflux across the intestinal wall. These natural compounds will likely prove useful lead structures in the development of treatments for diabetes and cancer. The review by Ganapathy, Thangaraju, Prasad, Martin and Singh [6] focuses on the fascinating mutual relationship between man and the prokaryotic content of his colonic lumen. The signalling factors are the short chain fatty acids (SCFA) Current Opinion in Pharmacology 2013, 13:843–846

butyrate and propionate produced in the colon by bacterial fermentation of non-digested dietary fibre. The SCFAs ‘signal’ by either undergoing transport by the sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8) or by binding to the SCFA receptors GPR109A and GPR43. The anti-inflammatory and tumour-suppressive functions associated with these transporters and receptors highlights them as potential targets for pharmacologists in the development of tools for the treatment of inflammatory bowel disorders and colonic cancer. Another absorptive transporter with potential for development as a target in cancer treatment is the protoncoupled folate transporter PCFT (SLC46A1). Zhao and Goldman [7] review the latest observations with this folate carrier which is expressed at the luminal surface in the small intestine and is defective in hereditary folate malabsorption. Antifolates used in cancer treatment are delivered intravenously but PCFT could play an important role in reabsorption from the gut lumen of those undergoing enterohepatic circulation. Antifolates with selectivity for PCFT (over the ubiquitous reduced folate carrier RFC (SLC19A1)) are being developed and the increased activity of PCFT at the acidic pH values found in solid tumours could favour this carrier as a route for targeted delivery of anticancer agents. Like PCFT, the di/tripeptide transporter PepT1 proton-coupled (SLC15A1) is also expressed at the brush-border surface of the human small intestine and is responsible for both nutrient and drug transport. PepT1 is perhaps the best characterised of all the absorptive SLC/solute transporters with potential as targets for oral drug delivery. Brandsch [8] summarises recent studies with PepT1 which is a major mechanism for the absorption of several b-lactam antibiotics and the anti-viral prodrug valacyclovir. Brandsch [8] also highlights the potential of a prodrug approach to improve oral bioavailability of poorly absorbed compounds and discusses recent developments with new PepT1 prodrug substrates of zanamivir, oseltamivir and didanosine. Targeting drugs to intestinal absorptive transporters to improve oral bioavailability requires detailed knowledge of the substrate specificity of each individual transport protein. There are many carrier proteins that could prove to be useful portals for drug transport across the brush-border membrane of the intestinal epithelium, which is perhaps the first major barrier to drug absorption. PCFT [7] and PepT1 [8] were chosen here as pardigms but many other transporters with similar potential as routes for drug transport across the wall of the human small intestine exist and they have been reviewed elsewhere [9,10]. The remaining three articles in this special edition focus on fluid and electrolyte transport in the gastrointestinal tract. Thiagarajah and Verkman [11] provide an excellent review of recent advances in the development of www.sciencedirect.com

Editorial overview Thwaites 845

anti-diarrhoeal agents. Enterotoxin-induced diarrhoea is a result of enhanced chloride and, therefore, fluid secretion across the human small intestinal epithelium. The final stage in chloride secretion in the intestine is exit across the luminal surface via chloride channels. High throughput screening has been used to identify inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) and Ca2+-activated chloride channels (CaCCs). In addition, as observed above [4,5] with some of the efflux pumps and absorptive transporters, natural components of diet have also been shown to modulate gut function and in this case electrolyte and fluid secretion. Thiagarajah and Verkman [11] discuss their recent findings that components found in red wine and a Thai herbal remedy can selectively inhibit chloride channel activity and intestinal fluid secretion. Although the emphasis here is on inhibitors of chloride channels, the change from a net absorptive to a net secretory state involves the coordinated activity of many types of membrane transport proteins some of which (e.g. potassium channels) could prove to be good alternative targets for pharmacologists to develop novel tools for treatment of secretory and inflammatory diarrhoeas. Other ion channel targets have been highlighted in an excellent review by Sandle [12] in a previous edition of this journal. In this volume, Gareau and Barrett [13] provide an update on other potential targets for treatment of inflammatory-associated diarrhoeas. As discussed by Ganapathy et al. [6] in relation to bacterialproduced SCFAs in the colon, the relationship between host and colonic microbiota may also provide tools for treatment of inflammatory-induced diarrhoea. Certain probiotics have been shown to regulate intestinal secretion both in vivo and in vitro by various effects including changes in expression of absorptive transporters such as the chloride/bicarbonate exchanger DRA (SLC26A3). As well as being important in chloride absorption, luminally expressed chloride/bicarbonate antiporters such as DRA or the putative anion transporter SLC26A6 are also important in bicarbonate secretion and epithelial protection in the gut. This topic is reviewed here by Seidler [14] who provides a comprehensive summary of the history of bicarbonate secretion in the gut. Seidler [14] summarises recent developments in the methodologies used to measure bicarbonate transport and provides an update on the complex regulatory networks involved in control of intestinal bicarbonate secretion. Although each of the independent reviews is comprehensive in nature, the topics are not meant to be viewed as exclusive of others. Clearly, there are many other transport proteins in the gastrointestinal tract that could be targets for pharmacologists and several are reviewed elsewhere in articles [e.g. 3,9,10,12,15] that complement those published in this volume. Overall, the field of membrane transport is advancing rapidly and, www.sciencedirect.com

unlike Canute, we should not attempt to hold back the tide of information heading our way but rather we must go with the flow. It seems likely that the extent of the role of membrane transporters in movement of material (nutrients, micronutrients, drugs, vitamins, electrolytes, fluid) across the wall of the gastrointestinal tract has been under appreciated in the past. Certainly, it is an area of some discussion in the literature [15]. Although passive transport will play a role in transmembrane movement of some lipophilic materials, it is important to acknowledge that evidence is now available to demonstrate clearly that several substances previously considered to move by passive means alone are now known to be substrates for carrier proteins. For every compound the adage is likely true that the lack of any demonstration of carrier-mediated transport does not necessarily equate to support for purely passive movement. Therefore, any future volume of Current Opinion in Pharmacology dedicated to membrane transporters will certainly include examples of new transporters and evidence for carrier-mediated transport of novel substrates. I would like to thank the excellent group of expert authors who have contributed to this volume of Current Opinion in Pharmacology. They have provided informative, critical and timely summaries of each of the 10 topics and highlight directions for future investigation. I would also like to give many thanks to Fred Kop and Pien van Spijker-Laumanns for their patience, support and guidance throughout the preparation of this volume.

References 1.

Misaka S, Mu¨ller F, Fromm MF: Clinical relevance of drug efflux pumps in the gut. Curr Opin Pharmacol 2013, 13:847-852.

2.

Tang SC, Hendrikx JJMA, Beijnen JH, Schinkel AH: Genetically modified mouse models for oral drug absorption and disposition. Curr Opin Pharmacol 2013, 13:853-858.

3.

van Waterschoot RA, Schinkel AH: A critical analysis of the interplay between cytochrome P450 3A and P-glycoprotein: recent insights from knockout and transgenic mice. Pharmacol Rev 2011, 63:390-410.

4.

Tamai I, Nakanishi T: OATP transport-mediated drug absorption and interaction. Curr Opin Pharmacol 2013, 13:859863.

5.

Wenzel U: Flavonoids as drugs at the small intestinal level. Curr Opin Pharmacol 2013, 13:864-868.

6.

Ganapathy V, Thangaraju M, Prasad PD, Martin PM, Singh N: Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host. Curr Opin Pharmacol 2013, 13:869-874.

7.

Zhao R, Goldman ID: The proton-coupled folate transporter: physiological and pharmacological roles. Curr Opin Pharmacol 2013, 13:875-880.

8.

Brandsch M: Drug transport via the intestinal peptide transporter PepT1. Curr Opin Pharmacol 2013, 13:881-887.

9.

Thwaites DT, Anderson CMH: H+-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physiol 2007, 92:603-619. Current Opinion in Pharmacology 2013, 13:843–846

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10. Anderson CMH, Thwaites DT: Hijacking solute carriers for proton-coupled drug transport. Physiology 2010, 25:364-377.

13. Gareau MG, Barrett KE: Fluid and electrolyte secretion in the inflamed gut: novel targets for treatment of inflammationinduced diarrhoea. Curr Opin Pharmacol 2013, 13:895-899.

11. Thiagarajah JR, Verkman AS: Chloride channel-targeted therapy for secretory diarrheas. Curr Opin Pharmacol 2013, 13:888-894.

14. Seidler U: Gastrointestinal HCO3S transport and epithelial protection in the gut: new techniques, transport pathways and regulatory pathways. Curr Opin Pharmacol 2013, 13:900-908.

12. Sandle GI: Infective and inflammatory diarrhoea: mechanisms and opportunities for novel therapies. Curr Opin Pharmacol 2011, 11:634-639.

15. Kell DB, Dobson PD: Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat Rev Drug Discov 2008, 7:205-220.

Current Opinion in Pharmacology 2013, 13:843–846

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Go with the flow - membrane transport in the gut.

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