Cyprotex is a specialist provider of ADME and PK services and offer a range of in vitro permeability and transporter assays.
|Permeability and Transporter Services|
|MDR1-MDCK permeability (P-gp substrate identification)|
|Wild type MDCK permeability|
|BCRP substrate identification|
|SLC transporter substrate identification (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1A2, OATP2B1, OAT2, OAT4, OCTN2, PEPT1, PEPT2, NTCP)|
|SLC transporter inhibition (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1A2, OATP2B1, OAT2, OAT4, OCTN2, PEPT1, PEPT2, NTCP)|
|Single and double transporter knockout cell-based service|
|Other transporter assays available on request|
The permeability of drugs is an important factor in oral absorption, BBB permeation and transport of drugs into tissues and across cell membranes. The permeability of a drug across a membrane is dependent on the passive permeability as well as the susceptibility of the drug to efflux or uptake by drug transporter proteins.
Cyprotex offer a number of different models to study permeability including Caco-2, MDR1-MDCK and PAMPA as well as a panel of transporter assays which cover the key transporters recommended in the regulatory guidelines. For more information on DDI studies, request our ADME guide or our DDI regulatory guidance booklet.
Drug transporters exist in many tissues including, but not limited to, the intestinal epithelia, the hepatocytes and bile canaliculi, the kidney proximal tubules and the brain capillary endothelial cells.
The main transporters in these tissues are illustrated below.
Understanding whether your compound interacts with drug transporters is an important stage in the drug development process. In vitro transporter interaction assays are used to identify if clinical drug-drug interaction studies are required.
The draft FDA guidance for industry on drug interaction studies (Feb 2012)1 and the European Medicines Agency (EMA) guideline on the investigation of drug interactions (adopted 2012)2 provides recommendations on the seven most relevant drug transporters for evaluation in the drug discovery and development process:
In addition to the main 7 transporters, the EMA also recommends preferably evaluating:
and suggests that the following transporters could also be considered:
In addition to these broadly recommended transporter studies, there are a number of other potentially clinically relevant transporters which may be important for particular drug-discovery programmes. These are discussed in the International Transporter Consortium (ITC) review papers published in March 20103 and July 20134.
Cyprotex provides an extensive portfolio of drug transporter services and provides support to in vitro drug interaction studies including data required for regulatory submission.
P-gp (P-glycoprotein) is one of the most well-recognized efflux transporters. It is expressed in many tissues, including the intestine, brain, and kidney. P-gp inhibition has been shown to be responsible for several clinical drug-drug interactions. For example, clarithromycin can inhibit the transport of the P-gp substrate digoxin, resulting in an elevation of plasma levels and a decrease in renal clearance5.
Recommendations for studying P-gp inhibition and substrate identification are outlined in the FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations, (2012)1 and in the EMA Guideline on the Investigation of Drug Interactions (Adopted 2012)2. Cyprotex follow the decision trees for identifying if an in vivo drug-drug interaction study is required using in vitro protocols recommended by the regulatory authorities.
Cyprotex offer a number of different options for evaluating P-gp interactions. These include;
Bidirectional Caco-2 permeability – Cyprotex offer a P-gp substrate identification assay using Caco-2 cells by evaluating bidirectional transport in the presence and absence of the P-gp inhibitor, verapamil.
Bidirectional MDR1-MDCK permeability – MDR1-MDCK cells overexpress human MDR1 in MDCK cells. By performing a bidirectional assay, it is possible to identify P-gp substrates and to screen for P-gp inhibitors. Evaluating efflux in the wild type MDCK cells, it is possible to rule out the involvement of any native activity in the parental cells.
BCRP (Breast Cancer Resistance Protein) is an efflux transporter expressed in several tissues such as the gastrointestinal tract, liver, brain endothelium, mammary tissue, testis, and placenta. BCRP is known to play a role in clinical drug-drug interactions. In addition, clinically relevant genetic polymorphisms have been shown to impact on the PK (e.g., irinotecan6, rosuvastatin7, sulfasalasine8 and topotecan9) and toxicity (e.g., gefitinib-induced diarrhea10) of marketed drugs. The draft FDA guidance1 and the EMA guidance2 recommend investigating BCRP due to BCRP's clinical importance in the absorption and disposition of drugs.
The draft FDA guidance1 and the EMA guidance2 recommend using Caco-2 to study BCRP interactions. Cyprotex identify BCRP substrates by investigating bidirectional Caco-2 permeability in the presence of a selective BCRP inhibitor, fumitremorgin C. We also use Caco-2 cells to characterize BCRP inhibitors using a range of inhibitor concentrations in the presence of the probe substrate estrone-3-sulphate.
Organic Anion Transporting Polypeptide 1B1 (OATP1B1) is expressed on the sinusoidal membrane of hepatocytes where it is responsible for the uptake of several marketed drugs including some statins11. There is evidence for clinical drug-drug interactions involving cyclosporine which appear to be mediated, at least in part, by inhibition of OATP1B112, 13.
The draft FDA guidance1 and the EMA guidance2 recommend investigating for potential OATP1B1 substrates and inhibitors due to the role of OATP1B1 in drug-drug interactions and the impact of genetic polymorphism of this transporter on therapy outcome and toxicity. According to the most recent regulatory guidance, it is only necessary to evaluate potential OATP1B1 substrates when hepatic clearance of the investigational drug is significant (e.g., hepatic elimination (hepatic or biliary clearance) is more than or equal to 25% of the total clearance).
Organic Anion Transporting Polypeptide 1B3 (OATP1B3) is an uptake transporter expressed on the sinusoidal membrane of hepatocytes. It has a substrate specificity that overlaps somewhat with OATP1B114. Because of the prominent expression of these transporters on the basolateral membrane of hepatocytes, they represent a critical mechanism for uptake of drugs into the liver.
The draft FDA guidance1 and the EMA guidance2 recommend the evaluation of new chemical entities for their potential to act as substrates or inhibitors of OATP1B3 in vitro. It is only necessary to evaluate potential OATP1B3 substrates when hepatic clearance of the investigational drug is significant (e.g., hepatic elimination (hepatic or biliary clearance) is more than or equal to 25% of the total clearance).
Organic Cation Transporter 2 (OCT2) is a member of the SLC family of transporters (SLC22A2). This transporter is expressed on the cells of the kidney proximal tubules where it is involved in the renal clearance of drug substrates15. Drug-drug interactions involving OCT2 may result in decreased renal clearance of the victim drug and a corresponding increase in exposure (e.g., cimetidine interaction with metformin16).
The draft FDA guidance1 and the EMA guidance2 recommend investigating for potential OCT2 substrates and inhibitors due to the role of OCT2 in drug-drug interactions. It is only necessary to evaluate potential OCT2 substrates when renal active secretion of the investigational drug is significant (e.g., active secretion by the kidney is more than or equal to 25% of total clearance).
Organic Anion Transporter 1 (OAT1) is part of the SLC superfamily (SLC22A6). It is a transmembrane protein expressed predominantly in the basolateral membrane of proximal tubular cells of the kidneys. It plays a central role in renal organic anion transport17. OAT1 is involved in the uptake of a wide range of relatively small and hydrophilic organic anions from plasma into the cytoplasm of the proximal tubular cells of the kidneys for subsequent exit across the apical membrane for excretion via the urine18. It has an essential role in the disposition of NSAIDs, antiviral drugs, diuretics, antitumor drugs and β-lactam antibiotics17.
The draft FDA guidance1 and the EMA guidance2 recommend investigating for potential OAT1 substrates and inhibitors due to the role of OAT1 in drug-drug interactions. It is only necessary to evaluate potential OAT1 substrates when renal active secretion of the investigational drug is significant (e.g., active secretion by the kidney is more than or equal to 25% of total clearance).
Organic Anion Transporter 3 (OAT3) is part of the SLC superfamily (SLC22A8). Like OAT1, it is primarily expressed in the basolateral membrane of proximal tubular cells of the kidneys, facilitating its role is in the renal transport of organic anions17.
OAT3 exhibits a broader substrate specificity than OAT1, and accepts amphipathic and hydrophilic organic anions and some organic cations17. Drugs which are renally cleared and are actively secreted by OATs may be susceptible to increases in AUC as a result of OAT3 inhibition. Examples of these clinically relevant interactions include the interaction of probenecid with acyclovir, resulting in a 32% decline in renal clearance, a 40% increase in AUC, and an 18% increase in the terminal plasma half-life of acyclovir following probenecid administration19.
The draft FDA guidance1 and the EMA guidance2 recommend investigating for potential OAT3 substrates and inhibitors due to the role of OAT3 in drug-drug interactions. It is only necessary to evaluate potential OAT3 substrates when renal active secretion of the investigational drug is significant (e.g., active secretion by the kidney is more than or equal to 25% of total clearance).
The Bile Salt Export Pump (BSEP) is a member of the ATP binding cassette family of transporters and is located on the canalicular membrane of hepatocytes. It is involved in transport of taurocholate and other cholate conjugates from hepatocytes to the bile and plays an important function in bile formation and bile flow20.
The European Medicines Agency2 suggests preferably evaluating the inhibitory potential of new chemical entities on the BSEP transporter.
Learn more about our BSEP interaction services.
Organic Cation Transporter 1 (OCT1) is a member of the SLC superfamily (SLC22A1) and is located on the basolateral membrane of hepatocytes, enterocytes, and renal proximal tubular cells21. It mediates facilitated transport of small (hydrophilic) organic cations22. The OCTs have been implicated in several clinically relevant drug interactions. For example co-administration of cimetidine with metformin increased the AUC of metformin by 50% and reduced the renal clearance by 27%16.
The European Medicines Agency2 suggests that the potential of new chemical entities for their ability to inhibit OCT1 in vitro could be considered.
The human multidrug and toxin extrusion (MATE)-type transporter 1 (hMATE1, SLC47A1) is a key transporter for the secretion of organic cations. MATE1 can either act as an uptake or efflux transporter, depending on an oppositely directed proton gradient as the driving force. Therefore, extracellular alkalinization or intracellular acidification increases MATE1-mediated uptake in vitro, whereas extracellular acidification increases efflux by MATE123. Although MATE1 has been detected in several tissues, the main organ of expression appears to be the kidney. It is specifically located in the brush border (apical) membrane of the proximal and distal convoluted tubules24. Single nucleotide polymorphisms (SNPs) in the SLC47A1 gene have been implicated in altered metformin disposition in humans25.
The European Medicines Agency2 suggests that the potential of new chemical entities for their ability to inhibit MATE1 in vitro could be considered.
The human multidrug and toxin extrusion transporter 2-K (MATE2-K, SLC47A2) is a splicing variant of hMATE2. MATE2-K is an H+/organic cation antiporter which is located exclusively in the kidney on the brush border membrane of proximal tubules26. It plays an important role in extruding organic cations into the kidney27. Substrates of MATE2-K include metformin, cimetidine, TEA and procainamide, and there is considerable overlap in terms of substrate specificity with the MATE1 transporter28.
The European Medicines Agency2 suggests that the potential of new chemical entities for their ability to inhibit MATE2 in vitro could be considered.
MRP2 (ABCC2) belongs to the ATP-binding cassette transporter superfamily. It is one of the major efflux transporters localized on the hepatic canalicular membrane in liver and plays a role in hepatobiliary secretion. MRP2 is also expressed on the luminal membrane of the intestine and on the apical membrane of proximal renal tubule endothelial cells where it is involved in the excretion of small organic anions.
Cyprotex can offer MRP2 interaction studies. Please email us for details.
Organic Anion Transporting Polypeptide 1A2 (OATP1A2) is a member of the SLC transporter family (SLCO1A2). Highest expression of OATP1A2 mRNA is observed in the brain, but it is also present in the liver, intestine, kidneys, lung and testes. OATP1A2 has a broad range of substrates including endogenous compounds such as bile acids, steroid hormones and their conjugates and thyroid hormones as well as various drugs such as fexofenadine, ouabain and methoxtrexate. The transport does exhibit pH dependency with methotrexate increasing 7‑fold at pH 5.0 compared with pH 7.429.
OATP1A2 is localized on the brush border membrane of enterocytes in the duodenum where it is thought to be involved in absorption and in the cholangiocytes of the liver where it is thought to be involved in reabsorption of xenobiotics excreted into the bile. It also plays a role in the renal transport and the blood brain barrier transport of xenobiotics. The transporter is thought to be important in breast cancer where mRNA expression in breast cancer tissue has been found to be almost 10‑fold higher than in healthy tissue, and it is believed that OATP1A2 may enhance hormone dependent breast cancer proliferation by facilitating estrone 3‑sulfate uptake in the cells29.
Organic Anion Transporting Polypeptide 2B1 (OATP2B1) is a member of the SLC transporter family (SLCO2B1). As well as being localized in the sinusoidal membrane of the liver where it is involved in uptake of drugs or endogenous substances and in the intestine where it plays a role in uptake and absorption, OATP2B1 is also expressed in the brain, lung, spleen, kidney, heart, placenta and ovaries30. OATP2B1 transport appears to be pH-dependent with an increased activity at acidic pH such as that observed in the weakly acidic intestinal30. The transporter is also expressed in a number of solid tumours. As the solid tumour microenvironment is acidic, it is thought OATP2B1 could also play a role in drug delivery to tumour cells31. Substrates of OATP2B1 include steroid conjugates, thyroid hormone and numerous drugs including statins30,32.
Organic Anion Transporter 2 (OAT2) is a member of the SLC transporter family (SLC22A7). Expression of OAT2 is primarily expressed in the basolateral membrane of renal proximal tubule cells and is involved in active renal secretion of drugs or endogenous molecules33. OAT2 is also expressed in the liver and several other tissues in the body34. Substrates for OAT2 include acetyl salicylate, prostaglandin E2, dicarboxylates, glutamates, PAH as well as some anitvirals34. Of particular note is the transport of the endogenous substrate, cGMP, and it is thought therefore that OAT2 may be involved in modulation of intracellular signalling.
OAT4 is a member of the SLC transporter family (SLC22A11). It is localized primarily in the syncytiotrophoblast cells of the placenta where it plays a role in regulating transport of hormones, drugs and toxins across the maternal-fetal barrier, and also in the apical membrane of renal proximal tubule cells where it is important for the reabsorption of organic anions, including sulfate conjugates34,35. Substrates of OAT4 include sulphated steroids, NSAIDs, anti-hypertensives, prostaglandins and uric acid34.
The organic cation / carnitine transporter 2 (OCTN2) is a member of the SLC transporter family (SLC22A5). It is expressed in the brush border membrane of the proximal renal tubule cells where it acts as a high affinity Na+/carnitine co-transporter and is responsible for the reabsorption of L‑carnitine and acetyl carnitine. These endogenous molecules are important in the transport of long chain fatty acids into mitochondria and subsequent energy production by β-oxidation36. OCTN2 is also expressed in skeletal muscle, placenta, heart, pancreas, liver, lung, intestine and brain tissue37. Transport can be bidirectional, with the direction dependent on the substrate. Other known substrates of OCTN2 include verapamil, cephaloridine and oxaliplatin37. Polymorphisms in OCTN2 have been associated with the clinical progression of intestinal inflammation in conditions such as Crohn's disease37.
Peptide transporter 1 (PEPT1) is a member of the SLC family of transporters (SLC15A1). It is a low affinity high capacity transporter which is proton dependent. PEPT1 is localized on the brush border membrane of the intestine and to a lesser extent on renal epithelial cells. It is also known to be present in certain cancer cells. The primary role of PEPT1 is the uptake of dipeptides, tripeptides or free amino acids in the small intestine following dietary protein digestion within the gastrointestinal tract38. Certain β-lactam antibiotics and anticancer agents are also substrates for PEPT1 in the intestine. Uptake by PEPT1 in the intestine is also a popular route for prodrug design for drug delivery. Prodrugs which have amino acids as promoieties have been designed to be substrates of PEPT1 to improve oral absorption and bioavailability. This has been successful in the case of anti-virals such as valacyclovir and valganciclovir39. There is also evidence of PEPT1 playing a role in the pathogenesis of intestinal inflammation40.
Peptide transporter 2 (PEPT2) is a member of the SLC transporter family (SLC15A2). It is a high affinity low capacity transporter. Like PEPT1, it is involved in the proton-coupled transport of dipeptides, tripeptides, amino acids and peptide-like drugs. PEPT2 is widely distributed in the body and is expressed in the kidney, central nervous system and lung as well as several other tissues41.
The sodium/taurocholate cotransporting polypeptide (NTCP) is a member of the SLC transporter family (SLC10A1). NTCP is present on the sinusoidal membrane of hepatocytes where it is responsible for transporting bile salts into hepatocytes as part of the enterohepatic recirculation process. This is a process whereby bile is secreted by the hepatocytes, stored in the gall bladder and secreted into the intestine, from which many of its constituents are reabsorbed and recirculate via the portal vein back to the liver for re-uptake by NTCP. Although bile salts are the main substrate for NTCP, other substrates include estrone 3‑sulfate, bromosulfophthalein, dehydroepiandrosterone sulfate and thyroid hormones42. It has also been reported that NTCP contributes significantly to active hepatocyte uptake of statins43.
As well as our standard range of transporter assays, Cyprotex can offer transporter knockout cell-based assays for MDR1 (P-gp), BCRP and MRP2. The cell lines were created by Sigma® Life Science using CompoZr® Zinc Finger Nuclease (ZFN) technology. Both single and double transporter knockout cells are available: MDR1 KO, BCRP KO, MRP2 KO, MDR1/BCRP KO, MDR1/MRP2 KO and BCRP/MRP2 KO. By comparing the wild type cells with the knockout cells it is possible to elucidate the transporter involved in the efflux without relying on specific chemical inhibitors for confirmation.
Sigma and CompoZr are registered trademarks of Sigma-Aldrich Co. LLC.
1 Draft FDA Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations, February 2012
2 The European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions (Adopted 2012)
3 The International Transporter Consortium (2010) Membrane transporters in drug
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4 Hillgren KM et al., (2013) Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther 94(1); 52-63
5 Wakasugi H et al. (1998) Effect of clarithromycin on renal excretion of digoxin: Interaction with P-glycoprotein. Clin Pharmacol Ther 64; 123–128
6 Zhou Q et al. (2005) Pharmacogenetic profiling across the irinotecan pathway in Asian patients with cancer. Br J Clin Pharmacol 59; 415–424
7 Zhang W et al. (2006) Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta 373; 99–103
8 Yamasaki Y et al. (2008) Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans. Clin Pharmacol Ther 84(1); 95–103.
9 Sparreboom A et al. (2005) Effect of ABCG2 genotype on the oral bioavailability of topotecan. Cancer Biol Ther 4; 650–658
10 Cusatis G et al. (2006) Pharmacogenetics of ABCG2 and adverse reactions to
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11 Chen C et al. (2005) Differential interaction of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos 33; 537–546
12 Neuvonen PJ et al. (2006) Drug interactions with lipid-lowering drugs: Mechanisms and clinical relevance. Clin Pharmacol Ther 80; 565–581
13 Shitara Y et al, (2003) Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug Interaction between cerivastatin and cyclosporin A. J Pharmacol Exp Ther 304; 610-616
14 Klaassen CD & Aleksunes LM (2010) Xenobiotic, bile acid, and cholesterol transporters: Function and regulation. Pharmacol Rev 62(1); 1–96
15 Aoki M et al., (2008) Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation. Am J Physiol Renal Physiol 295; F165-F170
16 Somogyi A et al. (1987) Reduction of metformin renal tubular secretion by cimetidine
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17 Nozaki Y et al., (2007) Characterization of the uptake of Organic Anion Transporter (OAT) 1 and OAT3 substrates by human kidney slices. J Pharmacol Exp Ther 321; 362–369
18 El-Sheikh AAK et al., (2008) Mechanisms of renal anionic drug transport. Eur J Pharmacol 585; 245-255
19 Laskin OL et al., (1982) Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans. Antimicrob Agents Chemother 21(5); 804-7
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22 Jonker JW et al, (2001) Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol Cell Biol 21(16); 5471–5477
23 Müller F and Fromm MF (2011) Transporter-mediated drug–drug interactions. Pharmacogenomics 12(7); 1017–1037
24 Meyer zu Schwabedissen HE et al, (2010) Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol 298; F997–F1005
25 Becker ML et al, (2010) Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response. Pharmacogenet Genomics 20(1); 38–44
26 Masuda S et al, (2006) Identification and functional characterization of a new human kidney–specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol 17; 2127–2135
27 Komatsu T et al, (2011) Characterization of the human MATE2 proton-coupled polyspecific organic cation exporter. Int J Biochem Cell Biol 43(6); 913–8
28 Tanihara Y et al, (2007) Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H+-organic cation antiporters. Biochem Pharmacol 74(2); 359–371
29 Zhou Y et al., (2015) Genetic polymorphisms and function of the organic anion-transporting polypeptide 1A2 and its clinical relevance in drug disposition. Pharmacology 95: 201-208.
30 Nakanishi T and Tamai I (2012) Genetic polymorphisms of OATP transporters and their impact on intestinal absorption and hepatic disposition of drugs. Drug Metab Pharmacokinet 27(1): 106-121.
31 Visentin M et al., (2012) Substrate and pH-specific antifolate transport mediated by organic anion-transporting polypeptide 2B1 (OATP2B1-SLCO2B1). Mol Pharmacol 81(2): 134-142
32 Roth M et al., (2012) OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol 165(5):1260-1287.
33 Cheng Y et al. (2012). Expression of organic anion transporter 2 in the human kidney and its potential role in the tubular secretion of guanine-containing antiviral drugs. Drug Metab Dispos 40(3): 617-624.
34 Nigam SK et al., (2015) The organic anion transporter family: a systems biology perspective. Physiol Rev 95(1): 83-123.
35 Ekaratanawong S et al., (2004) Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules. J Pharmacol Sci 94: 297-304.
36 Ohnishi S et al., (2008) Role of Na+/L-cartinine transporter (OCTN2) in renal handling of pivaloylcarnitiine and valproylcarnitine formed during pivalic acid-containing prodrugs and valproic acid treatment. Drug Metab Pharmacokinet 23(4): 293-303
37 Park HJ et al., (2016) Identification of OCTN2 variants and their association with phenotypes of Crohn’s disease in a Korean population. Sci. Rep. 6: 22887
38 Spanier B (2014) Transcriptional and functional regulation of the intestinal peptide transporter PEPT1. J Physiol 592: 871-879
39 Gupta D et al., (2013) Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue. Mol Pharm 10(2): 512-522
40 Ingersoll SA et al., (2012) The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 302(5); G484-92
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42 Trauner M & Boyer JL (2003) Bile salt transporters: molecular characterisation, function and regulation. Physiol Rev 83(2): 633-671.
43 Bi YA et al., (2013) Quantitative assessment of the contribution of sodium-dependent taurocholate co-transporting polypeptide (NTCP) to the hepatic uptake of rosuvastatin, pitavastatin and fluvastatin. Biopharm Drug Dispos 34(8): 452-461.