Intestinal Transporter-Associated Drug Absorption and Toxicity

  • Yaru Xue
  • Chenhui Ma
  • Imad HannaEmail author
  • Guoyu PanEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1141)


Oral drug administration is the most favorable route of drug administration in the clinic. Intestinal transporters have been shown to play a significant role in the rate and extent of drug absorption of some, but not all, drug molecules. Due to the heterogeneous expression of multiple transporters along the intestine, the preferential absorption sites for drugs may vary significantly. In this chapter, we aim to summarize the current research on the expression, localization, function, and regulation of human intestinal transporters implicated in altering the absorption of low to medium molecular weight drug molecules. The role played by bile acid transport proteins (e.g., ASBT and OST-α/β) is included in the discussion. The synergistic action of intestinal drug metabolism and transport is also discussed. Despite the complicated regulatory factors, the biopharmaceutics drug disposition classification system (BDDCS) put forward by Wu and Benet may help us better predict the effect of transporters on drug absorption. The drug-induced toxicity in the intestine, which may result from drug-drug interaction, gut microbiota, and bile salt toxicity, is also discussed.


Intestinal transporter Drug absorption Bile acid transport BDDCS Drug-induced toxicity 



This chapter was completed with the help of Xin Luo and Chen Ma.


  1. Abuasal BS, Bolger MB, Walker DK, Kaddoumi A (2012) In silico modeling for the nonlinear absorption kinetics of UK-343,664: a P-gp and CYP3A4 substrate. Mol Pharm 9:492–504CrossRefPubMedPubMedCentralGoogle Scholar
  2. Acimovic Y, Coe IR (2002) Molecular evolution of the equilibrative nucleoside transporter family: identification of novel family members in prokaryotes and eukaryotes. Mol Biol Evol 19:2199–2210CrossRefPubMedPubMedCentralGoogle Scholar
  3. Adachi Y, Suzuki H, Schinkel AH, Sugiyama Y (2005) Role of breast cancer resistance protein (Bcrp1/Abcg2) in the extrusion of glucuronide and sulfate conjugates from enterocytes to intestinal lumen. Mol Pharmacol 67:923–928CrossRefPubMedPubMedCentralGoogle Scholar
  4. Aiba T, Susa M, Fukumori S, Hashimoto Y (2005) The effects of culture conditions on CYP3A4 and MDR1 mRNA induction by 1alpha,25-dihydroxyvitamin D(3) in human intestinal cell lines, Caco-2 and LS180. Drug Metab Pharmacokinet 20:268–274CrossRefPubMedPubMedCentralGoogle Scholar
  5. Akamine Y, Miura M, Sunagawa S, Kagaya H, Yasui-Furukori N, Uno T (2010) Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers. Xenobiotica 40:782–789CrossRefPubMedPubMedCentralGoogle Scholar
  6. Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R et al (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323:1718–1722CrossRefPubMedPubMedCentralGoogle Scholar
  7. Amphoux A, Vialou V, Drescher E, Bruss M, Mannoury La Cour C, Rochat C et al (2006) Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 50:941–952CrossRefPubMedPubMedCentralGoogle Scholar
  8. Annaert P, Ye ZW, Stieger B, Augustijns P (2010) Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica 40:163–176CrossRefPubMedPubMedCentralGoogle Scholar
  9. Arana MR, Tocchetti GN, Rigalli JP, Mottino AD, Villanueva SS (2016) Physiological and pathophysiological factors affecting the expression and activity of the drug transporter MRP2 in intestine. Impact on its function as membrane barrier. Pharmacol Res 109:32–44CrossRefPubMedPubMedCentralGoogle Scholar
  10. Arimori K, Kuroki N, Hidaka M, Iwakiri T, Yamsaki K, Okumura M et al (2003) Effect of P-glycoprotein modulator, cyclosporin A, on the gastrointestinal excretion of irinotecan and its metabolite SN-38 in rats. Pharm Res 20:910–917CrossRefGoogle Scholar
  11. Ashida K, Katsura T, Motohashi H, Saito H, Inui K (2002) Thyroid hormone regulates the activity and expression of the peptide transporter PEPT1 in Caco-2 cells. Am J Physiol Gastrointest Liver Physiol 282:G617–G623CrossRefGoogle Scholar
  12. Avissar NE, Ziegler TR, Wang HT, Gu LH, Miller JH, Iannoli P et al (2001) Growth factors regulation of rabbit sodium-dependent neutral amino acid transporter ATB0 and oligopeptide transporter 1 mRNAs expression after enteretomy. JPEN J Parenter Enteral Nutr 25:65–72CrossRefGoogle Scholar
  13. Azevedo HS, Pashkuleva I (2015) Biomimetic supramolecular designs for the controlled release of growth factors in bone regeneration. Adv Drug Deliv Rev 94:63–76CrossRefGoogle Scholar
  14. Babusukumar U, Wang T, Mcguire E, Broeckel U, Kugathasan S (2006) Contribution of OCTN variants within the IBD5 locus to pediatric onset Crohn’s disease. Am J Gastroenterol 101:1354–1361CrossRefGoogle Scholar
  15. Bachmakov I, Glaeser H, Fromm MF, Konig J (2008) Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on organic anion transporting polypeptides and organic cation transporter 1. Diabetes 57:1463–1469CrossRefGoogle Scholar
  16. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) Grapefruit juice-drug interactions. Br J Clin Pharmacol 46:101–110CrossRefPubMedPubMedCentralGoogle Scholar
  17. Balimane PV, Tamai I, Guo A, Nakanishi T, Kitada H, Leibach FH et al (1998) Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem Biophys Res Commun 250:246–251CrossRefGoogle Scholar
  18. Ballatori N, Fang F, Christian WV, Li N, Hammond CL (2008) Ostalpha-Ostbeta is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liver. Am J Physiol Gastrointest Liver Physiol 295:G179–G186CrossRefPubMedPubMedCentralGoogle Scholar
  19. Ballatori N, Christian WV, Wheeler SG, Hammond CL (2013) The heteromeric organic solute transporter, OSTalpha-OSTbeta/SLC51: a transporter for steroid-derived molecules. Mol Asp Med 34:683–692CrossRefGoogle Scholar
  20. Barnes K, Dobrzynski H, Foppolo S, Beal PR, Ismat F, Scullion ER et al (2006) Distribution and functional characterization of equilibrative nucleoside transporter-4, a novel cardiac adenosine transporter activated at acidic pH. Circ Res 99:510–519CrossRefGoogle Scholar
  21. Barrios JM, Lichtenberger LM (2000) Role of biliary phosphatidylcholine in bile acid protection and NSAID injury of the ileal mucosa in rats. Gastroenterology 118:1179–1186CrossRefGoogle Scholar
  22. Bene J, Magyari L, Talian G, Komlosi K, Gasztonyi B, Tari B et al (2006) Prevalence of SLC22A4, SLC22A5 and CARD15 gene mutations in Hungarian pediatric patients with Crohn’s disease. World J Gastroenterol 12:5550–5553CrossRefPubMedPubMedCentralGoogle Scholar
  23. Benet LZ (2009) The drug transporter-metabolism alliance: uncovering and defining the interplay. Mol Pharm 6:1631–1643CrossRefPubMedPubMedCentralGoogle Scholar
  24. Benet LZ, Cummins CL, Wu CY (2004) Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int J Pharm 277:3–9CrossRefGoogle Scholar
  25. Benet LZ, Hosey CM, Ursu O, Oprea TI (2016) BDDCS, the rule of 5 and drugability. Adv Drug Deliv Rev 101:89–98CrossRefPubMedPubMedCentralGoogle Scholar
  26. Benz-De Bretagne I, Zahr N, Le Gouge A, Hulot JS, Houillier C, Hoang-Xuan K et al (2014) Urinary coproporphyrin I/(I + III) ratio as a surrogate for MRP2 or other transporter activities involved in methotrexate clearance. Br J Clin Pharmacol 78:329–342CrossRefPubMedPubMedCentralGoogle Scholar
  27. Bernsdorf A, Giessmann T, Modess C, Wegner D, Igelbrink S, Hecker U et al (2006) Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms. Br J Clin Pharmacol 61:440–450CrossRefPubMedPubMedCentralGoogle Scholar
  28. Beuling E, Kerkhof IM, Nicksa GA, Giuffrida MJ, Haywood J, Aan De Kerk DJ et al (2010) Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine. Gut 59:888–895CrossRefPubMedPubMedCentralGoogle Scholar
  29. Bikhazi AB, Skoury MM, Zwainy DS, Jurjus AR, Kreydiyyeh SI, Smith DE et al (2004) Effect of diabetes mellitus and insulin on the regulation of the PepT 1 symporter in rat jejunum. Mol Pharm 1:300–308CrossRefGoogle Scholar
  30. Bjarnason I, Hayllar J, Macpherson AJ, Russell AS (1993) Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 104:1832–1847CrossRefGoogle Scholar
  31. Brambila-Tapia AJ (2013) MDR1 (ABCB1) polymorphisms: functional effects and clinical implications. Rev Investig Clin 65:445–454Google Scholar
  32. Brandsch M (2013) Drug transport via the intestinal peptide transporter PepT1. Curr Opin Pharmacol 13:881–887CrossRefGoogle Scholar
  33. Bruyere A, Decleves X, Bouzom F, Ball K, Marques C, Treton X et al (2010) Effect of variations in the amounts of P-glycoprotein (ABCB1), BCRP (ABCG2) and CYP3A4 along the human small intestine on PBPK models for predicting intestinal first pass. Mol Pharm 7:1596–1607CrossRefGoogle Scholar
  34. Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M (2005) A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem 386:503–513CrossRefGoogle Scholar
  35. Cascorbi I (2011) P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations. Handb Exp Pharmacol 201:261–283CrossRefGoogle Scholar
  36. Chan LM, Lowes S, Hirst BH (2004) The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 21:25–51CrossRefGoogle Scholar
  37. Chaudhary R, Singh B, Kumar M, Gakhar SK, Saini AK, Parmar VS et al (2015) Role of single nucleotide polymorphisms in pharmacogenomics and their association with human diseases. Drug Metab Rev 47:281–290CrossRefGoogle Scholar
  38. Chavez-Talavera O, Tailleux A, Lefebvre P, Staels B (2017) Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 152:1679–1694 e1673CrossRefGoogle Scholar
  39. Chayen R, Rosenthal T (1991) Interaction of citrus juices with felodipine and nifedipine. Lancet 337:854CrossRefGoogle Scholar
  40. Chen X, Chen F, Liu S, Glaeser H, Dawson PA, Hofmann AF et al (2006) Transactivation of rat apical sodium-dependent bile acid transporter and increased bile acid transport by 1alpha,25-dihydroxyvitamin D3 via the vitamin D receptor. Mol Pharmacol 69:1913–1923CrossRefGoogle Scholar
  41. Chen XW, Sneed KB, Pan SY, Cao C, Kanwar JR, Chew H et al (2012) Herb-drug interactions and mechanistic and clinical considerations. Curr Drug Metab 13:640–651CrossRefGoogle Scholar
  42. Chen F, Wen Q, Jiang J, Li HL, Tan YF, Li YH et al (2016) Could the gut microbiota reconcile the oral bioavailability conundrum of traditional herbs? J Ethnopharmacol 179:253–264CrossRefGoogle Scholar
  43. Cho HY, Yoo HD, Lee YB (2010) Influence of ABCB1 genetic polymorphisms on the pharmacokinetics of levosulpiride in healthy subjects. Neuroscience 169:378–387CrossRefGoogle Scholar
  44. Chow EC, Sun H, Khan AA, Groothuis GM, Pang KS (2010) Effects of 1alpha,25-dihydroxyvitamin D3 on transporters and enzymes of the rat intestine and kidney in vivo. Biopharm Drug Dispos 31:91–108PubMedGoogle Scholar
  45. Chu XY, Kato Y, Niinuma K, Sudo KI, Hakusui H, Sugiyama Y (1997a) Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J Pharmacol Exp Ther 281:304–314PubMedGoogle Scholar
  46. Chu XY, Kato Y, Sugiyama Y (1997b) Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats. Cancer Res 57:1934–1938PubMedGoogle Scholar
  47. Chu XY, Kato Y, Ueda K, Suzuki H, Niinuma K, Tyson CA et al (1998) Biliary excretion mechanism of CPT-11 and its metabolites in humans: involvement of primary active transporters. Cancer Res 58:5137–5143PubMedGoogle Scholar
  48. Claudel T, Zollner G, Wagner M, Trauner M (2011) Role of nuclear receptors for bile acid metabolism, bile secretion, cholestasis, and gallstone disease. Biochim Biophys Acta 1812:867–878CrossRefGoogle Scholar
  49. Coon S, Kekuda R, Saha P, Sundaram U (2010) Glucocorticoids differentially regulate Na-bile acid cotransport in normal and chronically inflamed rabbit ileal villus cells. Am J Physiol Gastrointest Liver Physiol 298:G675–G682CrossRefPubMedPubMedCentralGoogle Scholar
  50. Cummins CL, Jacobsen W, Benet LZ (2002) Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 300:1036–1045CrossRefPubMedPubMedCentralGoogle Scholar
  51. Cummins CL, Salphati L, Reid MJ, Benet LZ (2003) In vivo modulation of intestinal CYP3A metabolism by P-glycoprotein: studies using the rat single-pass intestinal perfusion model. J Pharmacol Exp Ther 305:306–314CrossRefPubMedPubMedCentralGoogle Scholar
  52. Dahan A, Amidon GL (2009) Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting. Am J Physiol Gastrointest Liver Physiol 297:G371–G377CrossRefPubMedPubMedCentralGoogle Scholar
  53. Darling RL, Romero JJ, Dial EJ, Akunda JK, Langenbach R, Lichtenberger LM (2004) The effects of aspirin on gastric mucosal integrity, surface hydrophobicity, and prostaglandin metabolism in cyclooxygenase knockout mice. Gastroenterology 127:94–104CrossRefPubMedPubMedCentralGoogle Scholar
  54. Darwich AS, Neuhoff S, Jamei M, Rostami-Hodjegan A (2010) Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: a simulation assessment using the “Advanced Dissolution, Absorption, Metabolism (ADAM)” model. Curr Drug Metab 11:716–729CrossRefPubMedPubMedCentralGoogle Scholar
  55. Dawson PA (2011) Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol:169–203Google Scholar
  56. Dawson PA, Karpen SJ (2015) Intestinal transport and metabolism of bile acids. J Lipid Res 56:1085–1099CrossRefPubMedPubMedCentralGoogle Scholar
  57. Dawson PA, Lan T, Rao A (2009) Bile acid transporters. J Lipid Res 50:2340–2357CrossRefPubMedPubMedCentralGoogle Scholar
  58. De Aguiar Vallim TQ, Tarling EJ, Edwards PA (2013) Pleiotropic roles of bile acids in metabolism. Cell Metab 17:657–669CrossRefPubMedPubMedCentralGoogle Scholar
  59. De Castro WV, Mertens-Talcott S, Derendorf H, Butterweck V (2007) Grapefruit juice-drug interactions: grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. J Pharm Sci 96:2808–2817CrossRefPubMedPubMedCentralGoogle Scholar
  60. Deeley RG, Westlake C, Cole SP (2006) Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev 86:849–899CrossRefPubMedPubMedCentralGoogle Scholar
  61. Di Paolo A, Bocci G, Danesi R, Del Tacca M (2006) Clinical pharmacokinetics of irinotecan-based chemotherapy in colorectal cancer patients. Curr Clin Pharmacol 1:311–323CrossRefPubMedPubMedCentralGoogle Scholar
  62. Dietrich CG, Geier A, Salein N, Lammert F, Roeb E, Oude Elferink RP et al (2004) Consequences of bile duct obstruction on intestinal expression and function of multidrug resistance-associated protein 2. Gastroenterology 126:1044–1053CrossRefPubMedPubMedCentralGoogle Scholar
  63. Djahanguiri B, Abtahi FS, Hemmati M (1973) Prevention of aspirin-induced gastric ulceration by bile duct or pylorus ligation in the rat. Gastroenterology 65:630–633CrossRefPubMedPubMedCentralGoogle Scholar
  64. Dohse M, Scharenberg C, Shukla S, Robey RW, Volkmann T, Deeken JF et al (2010) Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab Dispos 38:1371–1380CrossRefPubMedPubMedCentralGoogle Scholar
  65. Drozdzik M, Groer C, Penski J, Lapczuk J, Ostrowski M, Lai Y et al (2014) Protein abundance of clinically relevant multidrug transporters along the entire length of the human intestine. Mol Pharm 11:3547–3555CrossRefPubMedPubMedCentralGoogle Scholar
  66. Drozdzik M, Busch D, Lapczuk J, Muller J, Ostrowski M, Kurzawski M et al (2018) Protein abundance of clinically relevant drug transporters in the human liver and intestine: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther 104(3):515–524CrossRefPubMedPubMedCentralGoogle Scholar
  67. Duan H, Wang J (2013) Impaired monoamine and organic cation uptake in choroid plexus in mice with targeted disruption of the plasma membrane monoamine transporter (Slc29a4) gene. J Biol Chem 288:3535–3544CrossRefPubMedPubMedCentralGoogle Scholar
  68. Dufek MB, Bridges AS, Thakker DR (2013a) Intestinal first-pass metabolism by cytochrome p450 and not p-glycoprotein is the major barrier to amprenavir absorption. Drug Metab Dispos 41:1695–1702CrossRefPubMedPubMedCentralGoogle Scholar
  69. Dufek MB, Knight BM, Bridges AS, Thakker DR (2013b) P-glycoprotein increases portal bioavailability of loperamide in mouse by reducing first-pass intestinal metabolism. Drug Metab Dispos 41:642–650CrossRefPubMedPubMedCentralGoogle Scholar
  70. El-Sheikh AA, Van Den Heuvel JJ, Koenderink JB, Russel FG (2007) Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport. J Pharmacol Exp Ther 320:229–235CrossRefPubMedPubMedCentralGoogle Scholar
  71. Engel K, Wang J (2005) Interaction of organic cations with a newly identified plasma membrane monoamine transporter. Mol Pharmacol 68:1397–1407CrossRefPubMedPubMedCentralGoogle Scholar
  72. Engel K, Zhou M, Wang J (2004) Identification and characterization of a novel monoamine transporter in the human brain. J Biol Chem 279:50042–50049CrossRefPubMedPubMedCentralGoogle Scholar
  73. Engevik AC, Goldenring JR (2018) Trafficking ion transporters to the apical membrane of polarized intestinal enterocytes. Cold Spring Harb Perspect Biol 10:pii: a027979CrossRefGoogle Scholar
  74. Englund G, Jacobson A, Rorsman F, Artursson P, Kindmark A, Ronnblom A (2007) Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1). Inflamm Bowel Dis 13:291–297CrossRefPubMedPubMedCentralGoogle Scholar
  75. Enright EF, Joyce SA, Gahan CG, Griffin BT (2017) Impact of gut microbiota-mediated bile acid metabolism on the solubilization capacity of bile salt micelles and drug solubility. Mol Pharm 14:1251–1263CrossRefPubMedPubMedCentralGoogle Scholar
  76. Enright EF, Griffin BT, Gahan CGM, Joyce SA (2018) Microbiome-mediated bile acid modification: role in intestinal drug absorption and metabolism. Pharmacol Res 133:170–186CrossRefPubMedPubMedCentralGoogle Scholar
  77. Estudante M, Morais JG, Soveral G, Benet LZ (2013) Intestinal drug transporters: an overview. Adv Drug Deliv Rev 65:1340–1356CrossRefPubMedPubMedCentralGoogle Scholar
  78. Fahrmayr C, Konig J, Auge D, Mieth M, Fromm MF (2012) Identification of drugs and drug metabolites as substrates of multidrug resistance protein 2 (MRP2) using triple-transfected MDCK-OATP1B1-UGT1A1-MRP2 cells. Br J Pharmacol 165:1836–1847CrossRefPubMedPubMedCentralGoogle Scholar
  79. Fang F, Christian WV, Gorman SG, Cui M, Huang J, Tieu K et al (2010) Neurosteroid transport by the organic solute transporter OSTalpha-OSTbeta. J Neurochem 115:220–233CrossRefPubMedPubMedCentralGoogle Scholar
  80. Ferraris RP, Choe JY, Patel CR (2018) Intestinal absorption of fructose. Annu Rev Nutr 38:41–67CrossRefPubMedPubMedCentralGoogle Scholar
  81. Ferrebee CB, Dawson PA (2015) Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids. Acta Pharm Sin B 5:129–134CrossRefPubMedPubMedCentralGoogle Scholar
  82. Fiorucci S, Distrutti E (2015) Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol Med 21:702–714CrossRefPubMedGoogle Scholar
  83. Fiorucci S, Mencarelli A, Cipriani S, Renga B, Palladino G, Santucci L et al (2011) Activation of the farnesoid-X receptor protects against gastrointestinal injury caused by non-steroidal anti-inflammatory drugs in mice. Br J Pharmacol 164:1929–1938CrossRefPubMedPubMedCentralGoogle Scholar
  84. Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I (1987) Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A 84:265–269CrossRefPubMedPubMedCentralGoogle Scholar
  85. Foster BC, Foster MS, Vandenhoek S, Krantis A, Budzinski JW, Arnason JT et al (2001) An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic. J Pharm Pharm Sci 4:176–184PubMedPubMedCentralGoogle Scholar
  86. Fujiya M, Inaba Y, Musch MW, Hu S, Kohgo Y, Chang EB (2011) Cytokine regulation of OCTN2 expression and activity in small and large intestine. Inflamm Bowel Dis 17:907–916CrossRefPubMedPubMedCentralGoogle Scholar
  87. Ganapathy ME, Huang W, Rajan DP, Carter AL, Sugawara M, Iseki K et al (2000) Beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter. J Biol Chem 275:1699–1707CrossRefPubMedPubMedCentralGoogle Scholar
  88. Gangopadhyay A, Thamotharan M, Adibi SA (2002) Regulation of oligopeptide transporter (Pept-1) in experimental diabetes. Am J Physiol Gastrointest Liver Physiol 283:G133–G138CrossRefPubMedPubMedCentralGoogle Scholar
  89. Geick A, Eichelbaum M, Burk O (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276:14581–14587CrossRefPubMedPubMedCentralGoogle Scholar
  90. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X et al (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236CrossRefGoogle Scholar
  91. Glaeser H, Bailey DG, Dresser GK, Gregor JC, Schwarz UI, Mcgrath JS et al (2007) Intestinal drug transporter expression and the impact of grapefruit juice in humans. Clin Pharmacol Ther 81:362–370CrossRefPubMedGoogle Scholar
  92. Graham DY, Opekun AR, Willingham FF, Qureshi WA (2005) Visible small-intestinal mucosal injury in chronic NSAID users. Clin Gastroenterol Hepatol 3:55–59CrossRefGoogle Scholar
  93. Gramatte T, Oertel R, Terhaag B, Kirch W (1996) Direct demonstration of small intestinal secretion and site-dependent absorption of the beta-blocker talinolol in humans. Clin Pharmacol Ther 59:541–549CrossRefPubMedGoogle Scholar
  94. Grandvuinet AS, Vestergaard HT, Rapin N, Steffansen B (2012) Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions. J Pharm Pharmacol 64:1523–1548CrossRefPubMedGoogle Scholar
  95. Green BR, Bain LJ (2013) Mrp2 is involved in the efflux and disposition of fosinopril. J Appl Toxicol 33:458–465CrossRefPubMedGoogle Scholar
  96. Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, Von Richter O, Zundler J et al (1999) The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 104:147–153CrossRefPubMedPubMedCentralGoogle Scholar
  97. Grube M, Kock K, Oswald S, Draber K, Meissner K, Eckel L et al (2006) Organic anion transporting polypeptide 2B1 is a high-affinity transporter for atorvastatin and is expressed in the human heart. Clin Pharmacol Ther 80:607–620CrossRefPubMedPubMedCentralGoogle Scholar
  98. Grube M, Reuther S, Meyer Zu Schwabedissen H, Kock K, Draber K, Ritter CA et al (2007) Organic anion transporting polypeptide 2B1 and breast cancer resistance protein interact in the transepithelial transport of steroid sulfates in human placenta. Drug Metab Dispos 35:30–35CrossRefPubMedPubMedCentralGoogle Scholar
  99. Grundemann D, Harlfinger S, Golz S, Geerts A, Lazar A, Berkels R et al (2005) Discovery of the ergothioneine transporter. Proc Natl Acad Sci U S A 102:5256–5261CrossRefPubMedPubMedCentralGoogle Scholar
  100. Guo X, Meng Q, Liu Q, Wang C, Sun H, Kaku T et al (2012) Construction, identification and application of HeLa cells stably transfected with human PEPT1 and PEPT2. Peptides 34:395–403CrossRefGoogle Scholar
  101. Guo M, Dai X, Hu D, Zhang Y, Sun Y, Ren W et al (2016) Potential pharmacokinetic effect of rifampicin on enrofloxacin in broilers: roles of P-glycoprotein and BCRP induction by rifampicin. Poult Sci 95:2129–2135CrossRefGoogle Scholar
  102. Han TK, Everett RS, Proctor WR, Ng CM, Costales CL, Brouwer KL et al (2013) Organic cation transporter 1 (OCT1/mOct1) is localized in the apical membrane of Caco-2 cell monolayers and enterocytes. Mol Pharmacol 84:182–189CrossRefGoogle Scholar
  103. Hendrikx JJ, Lagas JS, Rosing H, Schellens JH, Beijnen JH, Schinkel AH (2013) P-glycoprotein and cytochrome P450 3A act together in restricting the oral bioavailability of paclitaxel. Int J Cancer 132:2439–2447CrossRefGoogle Scholar
  104. Hilgendorf C, Ahlin G, Seithel A, Artursson P, Ungell AL, Karlsson J (2007) Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metab Dispos 35:1333–1340CrossRefGoogle Scholar
  105. Hillgren KM, Keppler D, Zur AA, Giacomini KM, Stieger B, Cass CE et al (2013) Emerging transporters of clinical importance: an update from the international transporter consortium. Clin Pharmacol Ther 94:52–63CrossRefGoogle Scholar
  106. Hindlet P, Bado A, Kamenicky P, Delomenie C, Bourasset F, Nazaret C et al (2009) Reduced intestinal absorption of dipeptides via PepT1 in mice with diet-induced obesity is associated with leptin receptor down-regulation. J Biol Chem 284:6801–6808CrossRefPubMedPubMedCentralGoogle Scholar
  107. Hirano M, Maeda K, Matsushima S, Nozaki Y, Kusuhara H, Sugiyama Y (2005) Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin. Mol Pharmacol 68:800–807CrossRefGoogle Scholar
  108. Hirano M, Maeda K, Shitara Y, Sugiyama Y (2006) Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Dispos 34:1229–1236CrossRefGoogle Scholar
  109. Ho PP, Steinman L (2016) Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 113:1600–1605CrossRefPubMedPubMedCentralGoogle Scholar
  110. Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ et al (2006) Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130:1793–1806CrossRefGoogle Scholar
  111. Ho RH, Choi L, Lee W, Mayo G, Schwarz UI, Tirona RG et al (2007) Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenet Genomics 17:647–656CrossRefPubMedPubMedCentralGoogle Scholar
  112. Holmes E, Li JV, Marchesi JR, Nicholson JK (2012) Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk. Cell Metab 16:559–564CrossRefGoogle Scholar
  113. Horikawa M, Kato Y, Sugiyama Y (2002) Reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats. Pharm Res 19:1345–1353CrossRefGoogle Scholar
  114. Hu S, Franke RM, Filipski KK, Hu C, Orwick SJ, De Bruijn EA et al (2008a) Interaction of imatinib with human organic ion carriers. Clin Cancer Res 14:3141–3148CrossRefGoogle Scholar
  115. Hu Y, Smith DE, Ma K, Jappar D, Thomas W, Hillgren KM (2008b) Targeted disruption of peptide transporter Pept1 gene in mice significantly reduces dipeptide absorption in intestine. Mol Pharm 5:1122–1130CrossRefPubMedPubMedCentralGoogle Scholar
  116. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA et al (2009) Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res 15:6062–6069CrossRefPubMedPubMedCentralGoogle Scholar
  117. Ieiri I, Suwannakul S, Maeda K, Uchimaru H, Hashimoto K, Kimura M et al (2007) SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 82:541–547CrossRefGoogle Scholar
  118. Ieiri I, Higuchi S, Sugiyama Y (2009) Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Expert Opin Drug Metab Toxicol 5:703–729CrossRefGoogle Scholar
  119. Ikegami T, Ha L, Arimori K, Latham P, Kobayashi K, Ceryak S et al (2002) Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea. Cancer Res 62:179–187PubMedGoogle Scholar
  120. Imai Y, Tsukahara S, Ishikawa E, Tsuruo T, Sugimoto Y (2002) Estrone and 17beta-estradiol reverse breast cancer resistance protein-mediated multidrug resistance. Jpn J Cancer Res 93:231–235CrossRefPubMedPubMedCentralGoogle Scholar
  121. Imanaga J, Kotegawa T, Imai H, Tsutsumi K, Yoshizato T, Ohyama T et al (2011) The effects of the SLCO2B1 c.1457C > T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans. Pharmacogenet Genomics 21:84–93CrossRefGoogle Scholar
  122. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, Mcdonald JG et al (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2:217–225CrossRefGoogle Scholar
  123. Ingersoll SA, Ayyadurai S, Charania MA, Laroui H, Yan Y, Merlin D (2012) The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 302:G484–G492CrossRefGoogle Scholar
  124. Ishiguro N, Maeda K, Saito A, Kishimoto W, Matsushima S, Ebner T et al (2008) Establishment of a set of double transfectants coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide. Drug Metab Dispos 36:796–805CrossRefPubMedPubMedCentralGoogle Scholar
  125. Ito K, Suzuki H, Horie T, Sugiyama Y (2005) Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport. Pharm Res 22:1559–1577CrossRefGoogle Scholar
  126. Iwanaga T, Kishimoto A (2015) Cellular distributions of monocarboxylate transporters: a review. Biomed Res 36:279–301CrossRefGoogle Scholar
  127. Jahnel J, Fickert P, Hauer AC, Hogenauer C, Avian A, Trauner M (2014) Inflammatory bowel disease alters intestinal bile acid transporter expression. Drug Metab Dispos 42:1423–1431CrossRefGoogle Scholar
  128. Jeon H, Jang IJ, Lee S, Ohashi K, Kotegawa T, Ieiri I et al (2013) Apple juice greatly reduces systemic exposure to atenolol. Br J Clin Pharmacol 75:172–179CrossRefGoogle Scholar
  129. Jia J, Puls D, Oswald S, Jedlitschky G, Kuhn JP, Weitschies W et al (2014) Characterization of the intestinal and hepatic uptake/efflux transport of the magnetic resonance imaging contrast agent gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid. Investig Radiol 49:78–86CrossRefGoogle Scholar
  130. Jia W, Xie G, Jia W (2018) Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol 15:111–128CrossRefGoogle Scholar
  131. Jin Y, Guo X, Yuan B, Yu W, Suo H, Li Z et al (2015) Disposition of astragaloside IV via enterohepatic circulation is affected by the activity of the intestinal microbiome. J Agric Food Chem 63:6084–6093CrossRefGoogle Scholar
  132. Jones RS, Morris ME (2016) Monocarboxylate transporters: therapeutic targets and prognostic factors in disease. Clin Pharmacol Ther 100:454–463CrossRefPubMedPubMedCentralGoogle Scholar
  133. Jones BR, Li W, Cao J, Hoffman TA, Gerk PM, Vore M (2005) The role of protein synthesis and degradation in the post-transcriptional regulation of rat multidrug resistance-associated protein 2 (Mrp2, Abcc2). Mol Pharmacol 68:701–710CrossRefGoogle Scholar
  134. Juan ME, Gonzalez-Pons E, Planas JM (2010) Multidrug resistance proteins restrain the intestinal absorption of trans-resveratrol in rats. J Nutr 140:489–495CrossRefGoogle Scholar
  135. Kalitsky-Szirtes J, Shayeganpour A, Brocks DR, Piquette-Miller M (2004) Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats. Drug Metab Dispos 32:20–27CrossRefGoogle Scholar
  136. Kashihara Y, Ieiri I, Yoshikado T, Maeda K, Fukae M, Kimura M et al (2017) Small-dosing clinical study: pharmacokinetic, pharmacogenomic (SLCO2B1 and ABCG2), and interaction (atorvastatin and grapefruit juice) profiles of 5 probes for OATP2B1 and BCRP. J Pharm Sci 106:2688–2694CrossRefGoogle Scholar
  137. Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM et al (2002) Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem 277:2908–2915CrossRefGoogle Scholar
  138. Keppler D (2014) The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia. Drug Metab Dispos 42:561–565CrossRefGoogle Scholar
  139. Kim DH (2018) Gut microbiota-mediated pharmacokinetics of ginseng saponins. J Ginseng Res 42:255–263CrossRefGoogle Scholar
  140. Kitamura Y, Kusuhara H, Sugiyama Y (2010) Functional characterization of multidrug resistance-associated protein 3 (mrp3/abcc3) in the basolateral efflux of glucuronide conjugates in the mouse small intestine. J Pharmacol Exp Ther 332:659–666CrossRefGoogle Scholar
  141. Kivisto KT, Niemi M (2007) Influence of drug transporter polymorphisms on pravastatin pharmacokinetics in humans. Pharm Res 24:239–247CrossRefGoogle Scholar
  142. Klaassen CD, Aleksunes LM (2010) Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev 62:1–96CrossRefPubMedPubMedCentralGoogle Scholar
  143. Klaassen CD, Cui JY (2015) Review: mechanisms of how the intestinal microbiota alters the effects of drugs and bile acids. Drug Metab Dispos 43:1505–1521CrossRefPubMedPubMedCentralGoogle Scholar
  144. Kobayashi K, Bouscarel B, Matsuzaki Y, Ceryak S, Kudoh S, Fromm H (1999) pH-dependent uptake of irinotecan and its active metabolite, SN-38, by intestinal cells. Int J Cancer 83:491–496CrossRefGoogle Scholar
  145. Kobayashi D, Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I (2003) Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane. J Pharmacol Exp Ther 306:703–708CrossRefGoogle Scholar
  146. Koepsell H, Lips K, Volk C (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227–1251CrossRefGoogle Scholar
  147. Kramer W (2011) Transporters, Trojan horses and therapeutics: suitability of bile acid and peptide transporters for drug delivery. Biol Chem 392:77–94CrossRefGoogle Scholar
  148. Krishnamurthy P, Xie T, Schuetz JD (2007) The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther 114:345–358CrossRefGoogle Scholar
  149. Kuno T, Hirayama-Kurogi M, Ito S, Ohtsuki S (2016) Effect of intestinal flora on protein expression of drug-metabolizing enzymes and transporters in the liver and kidney of germ-free and antibiotics-treated mice. Mol Pharm 13:2691–2701CrossRefGoogle Scholar
  150. Kunta JR, Sinko PJ (2004) Intestinal drug transporters: in vivo function and clinical importance. Curr Drug Metab 5:109–124CrossRefGoogle Scholar
  151. Kurata Y, Ieiri I, Kimura M, Morita T, Irie S, Urae A et al (2002) Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 72:209–219CrossRefGoogle Scholar
  152. Lan T, Rao A, Haywood J, Kock ND, Dawson PA (2012) Mouse organic solute transporter alpha deficiency alters FGF15 expression and bile acid metabolism. J Hepatol 57:359–365CrossRefPubMedPubMedCentralGoogle Scholar
  153. Lee W, Glaeser H, Smith LH, Roberts RL, Moeckel GW, Gervasini G et al (2005) Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J Biol Chem 280:9610–9617CrossRefGoogle Scholar
  154. Lemos C, Giovannetti E, Zucali PA, Assaraf YG, Scheffer GL, Van Der Straaten T et al (2011) Impact of ABCG2 polymorphisms on the clinical outcome and toxicity of gefitinib in non-small-cell lung cancer patients. Pharmacogenomics 12:159–170CrossRefPubMedPubMedCentralGoogle Scholar
  155. Letschert K, Faulstich H, Keller D, Keppler D (2006) Molecular characterization and inhibition of amanitin uptake into human hepatocytes. Toxicol Sci 91:140–149CrossRefGoogle Scholar
  156. Li T, Chiang JY (2014) Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 66:948–983CrossRefPubMedPubMedCentralGoogle Scholar
  157. Li H, Jia W (2013) Cometabolism of microbes and host: implications for drug metabolism and drug-induced toxicity. Clin Pharmacol Ther 94:574–581CrossRefGoogle Scholar
  158. Li J, Wang Y, Zhang W, Huang Y, Hein K, Hidalgo IJ (2012) The role of a basolateral transporter in rosuvastatin transport and its interplay with apical breast cancer resistance protein in polarized cell monolayer systems. Drug Metab Dispos 40:2102–2108CrossRefGoogle Scholar
  159. Li M, De Graaf IA, Siissalo S, De Jager MH, Van Dam A, Groothuis GM (2016) The consequence of drug-drug interactions influencing the interplay between P-glycoprotein and cytochrome P450 3a: an ex vivo study with rat precision-cut intestinal slices. Drug Metab Dispos 44:683–691CrossRefGoogle Scholar
  160. Li M, De Graaf IA, Van De Steeg E, De Jager MH, Groothuis GM (2017a) The consequence of regional gradients of P-gp and CYP3A4 for drug-drug interactions by P-gp inhibitors and the P-gp/CYP3A4 interplay in the human intestine ex vivo. Toxicol in Vitro 40:26–33CrossRefGoogle Scholar
  161. Li Y, Hafey MJ, Duong H, Evers R, Cheon K, Holder DJ et al (2017b) Antibiotic-induced elevations of plasma bile acids in rats independent of BSEP inhibition. Toxicol Sci 157:30–40PubMedGoogle Scholar
  162. Li Y, Tang R, Leung PSC, Gershwin ME, Ma X (2017c) Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases. Autoimmun Rev 16:885–896CrossRefGoogle Scholar
  163. Ligumsky M, Golanska EM, Hansen DG, Kauffman GL Jr (1983) Aspirin can inhibit gastric mucosal cyclo-oxygenase without causing lesions in rat. Gastroenterology 84:756–761CrossRefGoogle Scholar
  164. Ligumsky M, Sestieri M, Karmeli F, Zimmerman J, Okon E, Rachmilewitz D (1990) Rectal administration of nonsteroidal antiinflammatory drugs. Effect on rat gastric ulcerogenicity and prostaglandin E2 synthesis. Gastroenterology 98:1245–1249CrossRefGoogle Scholar
  165. Lilja JJ, Backman JT, Laitila J, Luurila H, Neuvonen PJ (2003) Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol. Clin Pharmacol Ther 73:192–198CrossRefPubMedPubMedCentralGoogle Scholar
  166. Lilja JJ, Juntti-Patinen L, Neuvonen PJ (2004) Orange juice substantially reduces the bioavailability of the beta-adrenergic-blocking agent celiprolol. Clin Pharmacol Ther 75:184–190CrossRefGoogle Scholar
  167. Liu H, Yang J, Du F, Gao X, Ma X, Huang Y et al (2009) Absorption and disposition of ginsenosides after oral administration of Panax notoginseng extract to rats. Drug Metab Dispos 37:2290–2298CrossRefGoogle Scholar
  168. Liu YH, Di YM, Zhou ZW, Mo SL, Zhou SF (2010) Multidrug resistance-associated proteins and implications in drug development. Clin Exp Pharmacol Physiol 37:115–120CrossRefGoogle Scholar
  169. Luo H, Zhang Y, Guo H, Zhang L, Li X, Ringseis R et al (2014) Transcriptional regulation of the human, porcine and bovine OCTN2 gene by PPARalpha via a conserved PPRE located in intron 1. BMC Genet 15:90CrossRefPubMedPubMedCentralGoogle Scholar
  170. Ma K, Hu Y, Smith DE (2012) Influence of fed-fasted state on intestinal PEPT1 expression and in vivo pharmacokinetics of glycylsarcosine in wild-type and Pept1 knockout mice. Pharm Res 29:535–545CrossRefGoogle Scholar
  171. Ma H, Sales VM, Wolf AR, Subramanian S, Matthews TJ, Chen M et al (2017) Attenuated effects of bile acids on glucose metabolism and insulin sensitivity in a male mouse model of prenatal undernutrition. Endocrinology 158:2441–2452CrossRefPubMedPubMedCentralGoogle Scholar
  172. Maeng HJ, Durk MR, Chow EC, Ghoneim R, Pang KS (2011) 1alpha,25-dihydroxyvitamin D3 on intestinal transporter function: studies with the rat everted intestinal sac. Biopharm Drug Dispos 32:112–125CrossRefGoogle Scholar
  173. Magnarin M, Morelli M, Rosati A, Bartoli F, Candussio L, Giraldi T et al (2004) Induction of proteins involved in multidrug resistance (P-glycoprotein, MRP1, MRP2, LRP) and of CYP 3A4 by rifampicin in LLC-PK1 cells. Eur J Pharmacol 483:19–28CrossRefGoogle Scholar
  174. Malik MY, Jaiswal S, Sharma A, Shukla M, Lal J (2016) Role of enterohepatic recirculation in drug disposition: cooperation and complications. Drug Metab Rev 48:281–327CrossRefGoogle Scholar
  175. Malingre MM, Beijnen JH, Rosing H, Koopman FJ, Jewell RC, Paul EM et al (2001a) Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients. Br J Cancer 84:42–47CrossRefPubMedPubMedCentralGoogle Scholar
  176. Malingre MM, Richel DJ, Beijnen JH, Rosing H, Koopman FJ, Ten Bokkel Huinink WW et al (2001b) Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol 19:1160–1166CrossRefPubMedGoogle Scholar
  177. Mayo SA, Song YK, Cruz MR, Phan TM, Singh KV, Garsin DA et al (2016) Indomethacin injury to the rat small intestine is dependent upon biliary secretion and is associated with overgrowth of enterococci. Phys Rep 4:e12725CrossRefGoogle Scholar
  178. Meerum Terwogt JM, Malingre MM, Beijnen JH, Ten Bokkel Huinink WW, Rosing H, Koopman FJ et al (1999) Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res 5:3379–3384PubMedPubMedCentralGoogle Scholar
  179. Meier Y, Eloranta JJ, Darimont J, Ismair MG, Hiller C, Fried M et al (2007) Regional distribution of solute carrier mRNA expression along the human intestinal tract. Drug Metab Dispos 35:590–594CrossRefPubMedGoogle Scholar
  180. Mendes C, Meirelles GC, Silva MS, Ponchel G (2018) Intestinal permeability determinants of norfloxacin in Ussing chamber model. Eur J Pharm Sci 121:236–242CrossRefPubMedGoogle Scholar
  181. Merlin D, Si-Tahar M, Sitaraman SV, Eastburn K, Williams I, Liu X et al (2001) Colonic epithelial hPepT1 expression occurs in inflammatory bowel disease: transport of bacterial peptides influences expression of MHC class 1 molecules. Gastroenterology 120:1666–1679CrossRefPubMedPubMedCentralGoogle Scholar
  182. Mimura Y, Yasujima T, Ohta K, Inoue K, Yuasa H (2017) Functional identification of plasma membrane monoamine transporter (PMAT/SLC29A4) as an atenolol transporter sensitive to flavonoids contained in apple juice. J Pharm Sci 106:2592–2598CrossRefPubMedGoogle Scholar
  183. Ming X, Knight BM, Thakker DR (2011) Vectorial transport of fexofenadine across Caco-2 cells: involvement of apical uptake and basolateral efflux transporters. Mol Pharm 8:1677–1686CrossRefPubMedGoogle Scholar
  184. Miyata M, Yamakawa H, Hamatsu M, Kuribayashi H, Takamatsu Y, Yamazoe Y (2011) Enterobacteria modulate intestinal bile acid transport and homeostasis through apical sodium-dependent bile acid transporter (SLC10A2) expression. J Pharmacol Exp Ther 336:188–196CrossRefPubMedGoogle Scholar
  185. Molinaro A, Wahlstrom A, Marschall HU (2018) Role of bile acids in metabolic control. Trends Endocrinol Metab 29:31–41CrossRefPubMedGoogle Scholar
  186. Mor-Cohen R, Zivelin A, Rosenberg N, Goldberg I, Seligsohn U (2005) A novel ancestral splicing mutation in the multidrug resistance protein 2 gene causes Dubin-Johnson syndrome in Ashkenazi Jewish patients. Hepatol Res 31:104–111CrossRefPubMedGoogle Scholar
  187. Morimoto K, Kishimura K, Nagami T, Kodama N, Ogama Y, Yokoyama M et al (2011) Effect of milk on the pharmacokinetics of oseltamivir in healthy volunteers. J Pharm Sci 100:3854–3861CrossRefPubMedGoogle Scholar
  188. Moscovitz JE, Yarmush G, Herrera-Garcia G, Guo GL, Aleksunes LM (2017) Differential regulation of intestinal efflux transporters by pregnancy in mice. Xenobiotica 47:989–997CrossRefPubMedPubMedCentralGoogle Scholar
  189. Motohashi H, Masuda S, Katsura T, Saito H, Sakamoto S, Uemoto S et al (2001) Expression of peptide transporter following intestinal transplantation in the rat. J Surg Res 99:294–300CrossRefPubMedGoogle Scholar
  190. Mouly S, Paine MF (2003a) P-glycoprotein increases from proximal to distal regions of human small intestine. Pharm Res 20:1595–1599CrossRefPubMedPubMedCentralGoogle Scholar
  191. Mouly S, Paine MF (2003b) P-glycoprotein increases from proximal to distal regions of human small intestine. Pharm Res 20:1595–1599CrossRefPubMedPubMedCentralGoogle Scholar
  192. Muller F, Fromm MF (2011) Transporter-mediated drug-drug interactions. Pharmacogenomics 12:1017–1037CrossRefPubMedGoogle Scholar
  193. Muller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M (2005) Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol 70:1851–1860CrossRefPubMedGoogle Scholar
  194. Muller J, Keiser M, Drozdzik M, Oswald S (2017) Expression, regulation and function of intestinal drug transporters: an update. Biol Chem 398:175–192CrossRefPubMedGoogle Scholar
  195. Murakami T, Takano M (2008) Intestinal efflux transporters and drug absorption. Expert Opin Drug Metab Toxicol 4:923–939CrossRefPubMedGoogle Scholar
  196. Nakanishi Y, Matsushita A, Matsuno K, Iwasaki K, Utoh M, Nakamura C et al (2010) Regional distribution of cytochrome p450 mRNA expression in the liver and small intestine of cynomolgus monkeys. Drug Metab Pharmacokinet 25:290–297CrossRefPubMedPubMedCentralGoogle Scholar
  197. Nakano T, Sekine S, Ito K, Horie T (2009) Correlation between apical localization of Abcc2/Mrp2 and phosphorylation status of ezrin in rat intestine. Drug Metab Dispos 37:1521–1527CrossRefPubMedPubMedCentralGoogle Scholar
  198. Ni Z, Bikadi Z, Rosenberg MF, Mao Q (2010) Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab 11:603–617CrossRefPubMedPubMedCentralGoogle Scholar
  199. Nie W, Sweetser S, Rinella M, Green RM (2005) Transcriptional regulation of murine Slc22a1 (Oct1) by peroxisome proliferator agonist receptor-alpha and -gamma. Am J Physiol Gastrointest Liver Physiol 288:G207–G212CrossRefGoogle Scholar
  200. Nies AT, Keppler D (2007) The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch 453:643–659CrossRefGoogle Scholar
  201. Nies AT, Schwab M, Keppler D (2008) Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opin Drug Metab Toxicol 4:545–568CrossRefGoogle Scholar
  202. Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y et al (2002) Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther 302:804–813CrossRefGoogle Scholar
  203. Nozawa T, Toyobuku H, Kobayashi D, Kuruma K, Tsuji A, Tamai I (2003) Enhanced intestinal absorption of drugs by activation of peptide transporter PEPT1 using proton-releasing polymer. J Pharm Sci 92:2208–2216CrossRefGoogle Scholar
  204. Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I (2004) Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther 308:438–445CrossRefPubMedPubMedCentralGoogle Scholar
  205. Ogihara T, Kano T, Wagatsuma T, Wada S, Yabuuchi H, Enomoto S et al (2009) Oseltamivir (tamiflu) is a substrate of peptide transporter 1. Drug Metab Dispos 37:1676–1681CrossRefPubMedPubMedCentralGoogle Scholar
  206. Ohura K, Nozawa T, Murakami K, Imai T (2011) Evaluation of transport mechanism of prodrugs and parent drugs formed by intracellular metabolism in Caco-2 cells with modified carboxylesterase activity: temocapril as a model case. J Pharm Sci 100:3985–3994CrossRefGoogle Scholar
  207. Okabe M, Szakacs G, Reimers MA, Suzuki T, Hall MD, Abe T et al (2008) Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters. Mol Cancer Ther 7:3081–3091CrossRefPubMedPubMedCentralGoogle Scholar
  208. Out C, Patankar JV, Doktorova M, Boesjes M, Bos T, De Boer S et al (2015) Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4. J Hepatol 63:697–704CrossRefPubMedPubMedCentralGoogle Scholar
  209. Pan X, Terada T, Irie M, Saito H, Inui K (2002) Diurnal rhythm of H+-peptide cotransporter in rat small intestine. Am J Physiol Gastrointest Liver Physiol 283:G57–G64CrossRefGoogle Scholar
  210. Pan X, Wang L, Grundemann D, Sweet DH (2013) Interaction of Ethambutol with human organic cation transporters of the SLC22 family indicates potential for drug-drug interactions during antituberculosis therapy. Antimicrob Agents Chemother 57:5053–5059CrossRefPubMedPubMedCentralGoogle Scholar
  211. Pang KS, Maeng HJ, Fan J (2009) Interplay of transporters and enzymes in drug and metabolite processing. Mol Pharm 6:1734–1755CrossRefGoogle Scholar
  212. Payen L, Sparfel L, Courtois A, Vernhet L, Guillouzo A, Fardel O (2002) The drug efflux pump MRP2: regulation of expression in physiopathological situations and by endogenous and exogenous compounds. Cell Biol Toxicol 18:221–233CrossRefGoogle Scholar
  213. Pellicoro A, Faber KN (2007) Review article: the function and regulation of proteins involved in bile salt biosynthesis and transport. Aliment Pharmacol Ther 26(Suppl 2):149–160CrossRefGoogle Scholar
  214. Peroni RN, Di Gennaro SS, Hocht C, Chiappetta DA, Rubio MC, Sosnik A et al (2011) Efavirenz is a substrate and in turn modulates the expression of the efflux transporter ABCG2/BCRP in the gastrointestinal tract of the rat. Biochem Pharmacol 82:1227–1233CrossRefGoogle Scholar
  215. Petrovic V, Teng S, Piquette-Miller M (2007) Regulation of drug transporters during infection and inflammation. Mol Interv 7:99–111CrossRefGoogle Scholar
  216. Polgar O, Robey RW, Bates SE (2008) ABCG2: structure, function and role in drug response. Expert Opin Drug Metab Toxicol 4:1–15CrossRefGoogle Scholar
  217. Poonkuzhali B, Lamba J, Strom S, Sparreboom A, Thummel K, Watkins P et al (2008) Association of breast cancer resistance protein/ABCG2 phenotypes and novel promoter and intron 1 single nucleotide polymorphisms. Drug Metab Dispos 36:780–795CrossRefGoogle Scholar
  218. Potthoff MJ, Kliewer SA, Mangelsdorf DJ (2012) Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev 26:312–324CrossRefPubMedPubMedCentralGoogle Scholar
  219. Rao A, Haywood J, Craddock AL, Belinsky MG, Kruh GD, Dawson PA (2008) The organic solute transporter alpha-beta, Ostalpha-Ostbeta, is essential for intestinal bile acid transport and homeostasis. Proc Natl Acad Sci U S A 105:3891–3896CrossRefPubMedPubMedCentralGoogle Scholar
  220. Reuter BK, Davies NM, Wallace JL (1997) Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation. Gastroenterology 112:109–117CrossRefGoogle Scholar
  221. Ringseis R, Luci S, Spielmann J, Kluge H, Fischer M, Geissler S et al (2008a) Clofibrate treatment up-regulates novel organic cation transporter (OCTN)-2 in tissues of pigs as a model of non-proliferating species. Eur J Pharmacol 583:11–17CrossRefGoogle Scholar
  222. Ringseis R, Ludi S, Hirche F, Eder K (2008b) Treatment with pharmacological peroxisome proliferator-activated receptor alpha agonist clofibrate increases intestinal carnitine absorption in rats. Pharmacol Res 58:58–64CrossRefGoogle Scholar
  223. Rodrigues AC (2010) Efflux and uptake transporters as determinants of statin response. Expert Opin Drug Metab Toxicol 6:621–632CrossRefGoogle Scholar
  224. Saeki M, Kurose K, Tohkin M, Hasegawa R (2008) Identification of the functional vitamin D response elements in the human MDR1 gene. Biochem Pharmacol 76:531–542CrossRefGoogle Scholar
  225. Satoh H, Yamashita F, Tsujimoto M, Murakami H, Koyabu N, Ohtani H et al (2005) Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos 33:518–523CrossRefGoogle Scholar
  226. Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K et al (2013) Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17:225–235CrossRefGoogle Scholar
  227. Schmiedlin-Ren P, Thummel KE, Fisher JM, Paine MF, Lown KS, Watkins PB (1997) Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1alpha,25-dihydroxyvitamin D3. Mol Pharmacol 51:741–754CrossRefGoogle Scholar
  228. Schoen RT, Vender RJ (1989) Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. Am J Med 86:449–458CrossRefGoogle Scholar
  229. Shimakura J, Terada T, Katsura T, Inui K (2005) Characterization of the human peptide transporter PEPT1 promoter: Sp1 functions as a basal transcriptional regulator of human PEPT1. Am J Physiol Gastrointest Liver Physiol 289:G471–G477CrossRefGoogle Scholar
  230. Shimakura J, Terada T, Shimada Y, Katsura T, Inui K (2006) The transcription factor Cdx2 regulates the intestine-specific expression of human peptide transporter 1 through functional interaction with Sp1. Biochem Pharmacol 71:1581–1588CrossRefGoogle Scholar
  231. Shirasaka Y, Suzuki K, Nakanishi T, Tamai I (2010) Intestinal absorption of HMG-CoA reductase inhibitor pravastatin mediated by organic anion transporting polypeptide. Pharm Res 27:2141–2149CrossRefGoogle Scholar
  232. Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA et al (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117:1422–1431CrossRefPubMedPubMedCentralGoogle Scholar
  233. Smith DE, Clemencon B, Hediger MA (2013) Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Asp Med 34:323–336CrossRefGoogle Scholar
  234. Song P, Rockwell CE, Cui JY, Klaassen CD (2015) Individual bile acids have differential effects on bile acid signaling in mice. Toxicol Appl Pharmacol 283:57–64CrossRefGoogle Scholar
  235. Soroka CJ, Ballatori N, Boyer JL (2010) Organic solute transporter, OSTalpha-OSTbeta: its role in bile acid transport and cholestasis. Semin Liver Dis 30:178–185CrossRefPubMedPubMedCentralGoogle Scholar
  236. Spahn-Langguth H, Langguth P (2001) Grapefruit juice enhances intestinal absorption of the P-glycoprotein substrate talinolol. Eur J Pharm Sci 12:361–367CrossRefGoogle Scholar
  237. Staley C, Weingarden AR, Khoruts A, Sadowsky MJ (2017) Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol 101:47–64CrossRefGoogle Scholar
  238. Stearns AT, Balakrishnan A, Rhoads DB, Ashley SW, Tavakkolizadeh A (2008) Diurnal rhythmicity in the transcription of jejunal drug transporters. J Pharmacol Sci 108:144–148CrossRefPubMedPubMedCentralGoogle Scholar
  239. Stephens RH, O’neill CA, Warhurst A, Carlson GL, Rowland M, Warhurst G (2001) Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia. J Pharmacol Exp Ther 296:584–591PubMedGoogle Scholar
  240. Stephens RH, Tanianis-Hughes J, Higgs NB, Humphrey M, Warhurst G (2002) Region-dependent modulation of intestinal permeability by drug efflux transporters: in vitro studies in mdr1a(−/−) mouse intestine. J Pharmacol Exp Ther 303:1095–1101CrossRefGoogle Scholar
  241. Sultan M, Rao A, Elpeleg O, Vaz FM, Abu-Libdeh B, Karpen SJ et al (2018) Organic solute transporter-beta (SLC51B) deficiency in two brothers with congenital diarrhea and features of cholestasis. Hepatology 68:590–598CrossRefPubMedPubMedCentralGoogle Scholar
  242. Sun R, Yang N, Kong B, Cao B, Feng D, Yu X et al (2017) Orally administered Berberine modulates hepatic lipid metabolism by altering microbial bile acid metabolism and the intestinal FXR signaling pathway. Mol Pharmacol 91:110–122CrossRefPubMedPubMedCentralGoogle Scholar
  243. Suzuki M, Suzuki H, Sugimoto Y, Sugiyama Y (2003) ABCG2 transports sulfated conjugates of steroids and xenobiotics. J Biol Chem 278:22644–22649CrossRefGoogle Scholar
  244. Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE et al (2011) Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci U S A 108(Suppl 1):4523–4530CrossRefGoogle Scholar
  245. Takanaga H, Ohnishi A, Matsuo H, Sawada Y (1998) Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in caco-2 cells. Biol Pharm Bull 21:1062–1066CrossRefGoogle Scholar
  246. Takano M, Yumoto R, Murakami T (2006) Expression and function of efflux drug transporters in the intestine. Pharmacol Ther 109:137–161CrossRefGoogle Scholar
  247. Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T et al (2002) Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther 300:918–924CrossRefGoogle Scholar
  248. Tamai I (2012) Oral drug delivery utilizing intestinal OATP transporters. Adv Drug Deliv Rev 64:508–514CrossRefGoogle Scholar
  249. Tamai I, Nakanishi T, Nakahara H, Sai Y, Ganapathy V, Leibach FH et al (1998) Improvement of L-dopa absorption by dipeptidyl derivation, utilizing peptide transporter PepT1. J Pharm Sci 87:1542–1546CrossRefGoogle Scholar
  250. Tamai I, Nezu J, Uchino H, Sai Y, Oku A, Shimane M et al (2000) Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun 273:251–260CrossRefGoogle Scholar
  251. Tan KP, Wang B, Yang M, Boutros PC, Macaulay J, Xu H et al (2010) Aryl hydrocarbon receptor is a transcriptional activator of the human breast cancer resistance protein (BCRP/ABCG2). Mol Pharmacol 78:175–185CrossRefGoogle Scholar
  252. Tang F, Horie K, Borchardt RT (2002) Are MDCK cells transfected with the human MRP2 gene a good model of the human intestinal mucosa? Pharm Res 19:773–779CrossRefGoogle Scholar
  253. Tate G, Li M, Suzuki T, Mitsuya T (2002) A new mutation of the ATP-binding cassette, sub-family C, member 2 (ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome. Genes Genet Syst 77:117–121CrossRefGoogle Scholar
  254. Thamotharan M, Bawani SZ, Zhou X, Adibi SA (1999) Hormonal regulation of oligopeptide transporter pept-1 in a human intestinal cell line. Am J Phys 276:C821–C826CrossRefGoogle Scholar
  255. Thorn M, Finnstrom N, Lundgren S, Rane A, Loof L (2005) Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract. Br J Clin Pharmacol 60:54–60CrossRefPubMedPubMedCentralGoogle Scholar
  256. Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR Jr, Chen X et al (2009) Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol 78:153–161CrossRefGoogle Scholar
  257. Toda T, Saito N, Ikarashi N, Ito K, Yamamoto M, Ishige A et al (2009) Intestinal flora induces the expression of Cyp3a in the mouse liver. Xenobiotica 39:323–334CrossRefGoogle Scholar
  258. Tsamandouras N, Guo Y, Wendling T, Hall S, Galetin A, Aarons L (2017) Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population. Pharmacogenet Genomics 27:27–38CrossRefGoogle Scholar
  259. Tzvetkov MV, Dos Santos Pereira JN, Meineke I, Saadatmand AR, Stingl JC, Brockmoller J (2013) Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration. Biochem Pharmacol 86:666–678CrossRefGoogle Scholar
  260. Van De Wetering K, Zelcer N, Kuil A, Feddema W, Hillebrand M, Vlaming ML et al (2007) Multidrug resistance proteins 2 and 3 provide alternative routes for hepatic excretion of morphine-glucuronides. Mol Pharmacol 72:387–394CrossRefGoogle Scholar
  261. Van Herwaarden AE, Wagenaar E, Merino G, Jonker JW, Rosing H, Beijnen JH et al (2007) Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk. Mol Cell Biol 27:1247–1253CrossRefGoogle Scholar
  262. Van Vlies N, Ferdinandusse S, Turkenburg M, Wanders RJ, Vaz FM (2007) PPAR alpha-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation. Biochim Biophys Acta 1767:1134–1142CrossRefGoogle Scholar
  263. Van Waterschoot RA, Ter Heine R, Wagenaar E, Van Der Kruijssen CM, Rooswinkel RW, Huitema AD et al (2010) Effects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir. Br J Pharmacol 160:1224–1233CrossRefPubMedPubMedCentralGoogle Scholar
  264. Varma MV, Ambler CM, Ullah M, Rotter CJ, Sun H, Litchfield J et al (2010) Targeting intestinal transporters for optimizing oral drug absorption. Curr Drug Metab 11:730–742CrossRefGoogle Scholar
  265. Varma MV, Gardner I, Steyn SJ, Nkansah P, Rotter CJ, Whitney-Pickett C et al (2012) pH-dependent solubility and permeability criteria for provisional biopharmaceutics classification (BCS and BDDCS) in early drug discovery. Mol Pharm 9:1199–1212CrossRefGoogle Scholar
  266. Vavricka SR, Musch MW, Fujiya M, Kles K, Chang L, Eloranta JJ et al (2006) Tumor necrosis factor-alpha and interferon-gamma increase PepT1 expression and activity in the human colon carcinoma cell line Caco-2/bbe and in mouse intestine. Pflugers Arch 452:71–80CrossRefGoogle Scholar
  267. Visentin M, Chang MH, Romero MF, Zhao R, Goldman ID (2012) Substrate- and pH-specific antifolate transport mediated by organic anion-transporting polypeptide 2B1 (OATP2B1-SLCO2B1). Mol Pharmacol 81:134–142CrossRefPubMedPubMedCentralGoogle Scholar
  268. Vivian D, Cheng K, Khurana S, Xu S, Kriel EH, Dawson PA et al (2014) In vivo performance of a novel fluorinated magnetic resonance imaging agent for functional analysis of bile acid transport. Mol Pharm 11:1575–1582CrossRefPubMedPubMedCentralGoogle Scholar
  269. Vlaming ML, Pala Z, Van Esch A, Wagenaar E, De Waart DR, Van De Wetering K et al (2009) Functionally overlapping roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate in vivo. Clin Cancer Res 15:3084–3093CrossRefGoogle Scholar
  270. Wagner CA, Lukewille U, Kaltenbach S, Moschen I, Broer A, Risler T et al (2000) Functional and pharmacological characterization of human Na(+)-carnitine cotransporter hOCTN2. Am J Physiol Ren Physiol 279:F584–F591CrossRefGoogle Scholar
  271. Wahlstrom A, Sayin SI, Marschall HU, Backhed F (2016) Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 24:41–50CrossRefGoogle Scholar
  272. Wang J (2016) The plasma membrane monoamine transporter (PMAT): structure, function, and role in organic cation disposition. Clin Pharmacol Ther 100:489–499CrossRefPubMedPubMedCentralGoogle Scholar
  273. Watanabe K, Terada K, Sato J (2003) Intestinal absorption of cephalexin in diabetes mellitus model rats. Eur J Pharm Sci 19:91–98CrossRefGoogle Scholar
  274. Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA et al (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 113:1408–1418CrossRefPubMedPubMedCentralGoogle Scholar
  275. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H et al (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439:484–489CrossRefGoogle Scholar
  276. Watanabe T, Maeda K, Nakai C, Sugiyama Y (2013a) Investigation of the effect of the uneven distribution of CYP3A4 and P-glycoprotein in the intestine on the barrier function against xenobiotics: a simulation study. J Pharm Sci 102:3196–3204CrossRefGoogle Scholar
  277. Watanabe T, Maeda K, Nakai C, Sugiyama Y (2013b) Investigation of the effect of the uneven distribution of CYP3A4 and P-glycoprotein in the intestine on the barrier function against xenobiotics: a simulation study. J Pharm Sci 102:3196–3204CrossRefGoogle Scholar
  278. Watkins PB (1997) The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv Drug Deliv Rev 27:161–170CrossRefGoogle Scholar
  279. Watson AJ, Lear PA, Montgomery A, Elliott E, Dacre J, Farthing MJ et al (1988) Water, electrolyte, glucose, and glycine absorption in rat small intestinal transplants. Gastroenterology 94:863–869CrossRefGoogle Scholar
  280. Weiss J, Rose J, Storch CH, Ketabi-Kiyanvash N, Sauer A, Haefeli WE et al (2007) Modulation of human BCRP (ABCG2) activity by anti-HIV drugs. J Antimicrob Chemother 59:238–245CrossRefGoogle Scholar
  281. Weiss J, Sauer A, Herzog M, Boger RH, Haefeli WE, Benndorf RA (2009) Interaction of thiazolidinediones (glitazones) with the ATP-binding cassette transporters P-glycoprotein and breast cancer resistance protein. Pharmacology 84:264–270CrossRefGoogle Scholar
  282. Westphal K, Weinbrenner A, Zschiesche M, Franke G, Knoke M, Oertel R et al (2000) Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction. Clin Pharmacol Ther 68:345–355CrossRefGoogle Scholar
  283. Wilson ID, Nicholson JK (2017) Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res 179:204–222CrossRefGoogle Scholar
  284. Wu CY, Benet LZ (2005) Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 22:11–23CrossRefGoogle Scholar
  285. Wu Y, Aquino CJ, Cowan DJ, Anderson DL, Ambroso JL, Bishop MJ et al (2013) Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes. J Med Chem 56:5094–5114CrossRefGoogle Scholar
  286. Xia L, Zhou M, Kalhorn TF, Ho HT, Wang J (2009) Podocyte-specific expression of organic cation transporter PMAT: implication in puromycin aminonucleoside nephrotoxicity. Am J Physiol Ren Physiol 296:F1307–F1313CrossRefGoogle Scholar
  287. Xu H, Kulkarni KH, Singh R, Yang Z, Wang SW, Tam VH et al (2009) Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides. Mol Pharm 6:1703–1715CrossRefPubMedPubMedCentralGoogle Scholar
  288. Yabuuchi H, Tamai I, Nezu J, Sakamoto K, Oku A, Shimane M et al (1999) Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther 289:768–773PubMedGoogle Scholar
  289. Yamada A, Maeda K, Kamiyama E, Sugiyama D, Kondo T, Shiroyanagi Y et al (2007) Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor. Drug Metab Dispos 35:2166–2176CrossRefGoogle Scholar
  290. Yamagata T, Kusuhara H, Morishita M, Takayama K, Benameur H, Sugiyama Y (2007) Improvement of the oral drug absorption of topotecan through the inhibition of intestinal xenobiotic efflux transporter, breast cancer resistance protein, by excipients. Drug Metab Dispos 35:1142–1148CrossRefGoogle Scholar
  291. Yamamoto-Furusho JK, Mendivil EJ, Villeda-Ramirez MA, Fonseca-Camarillo G, Barreto-Zuniga R (2011) Gene expression of carnitine organic cation transporters 1 and 2 (OCTN) is downregulated in patients with ulcerative colitis. Inflamm Bowel Dis 17:2205–2206CrossRefGoogle Scholar
  292. Yamashiro W, Maeda K, Hirouchi M, Adachi Y, Hu Z, Sugiyama Y (2006) Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dispos 34:1247–1254CrossRefGoogle Scholar
  293. Yazdanian M, Glynn SL, Wright JL, Hawi A (1998) Correlating partitioning and caco-2 cell permeability of structurally diverse small molecular weight compounds. Pharm Res 15:1490–1494CrossRefGoogle Scholar
  294. Yu XQ, Xue CC, Wang G, Zhou SF (2007) Multidrug resistance associated proteins as determining factors of pharmacokinetics and pharmacodynamics of drugs. Curr Drug Metab 8:787–802CrossRefGoogle Scholar
  295. Yu J, Zhou Z, Tay-Sontheimer J, Levy RH, Ragueneau-Majlessi I (2017) Intestinal drug interactions mediated by OATPs: a systematic review of preclinical and clinical findings. J Pharm Sci 106:2312–2325CrossRefPubMedPubMedCentralGoogle Scholar
  296. Zelcer N, Van De Wetering K, Hillebrand M, Sarton E, Kuil A, Wielinga PR et al (2005) Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc Natl Acad Sci U S A 102:7274–7279CrossRefPubMedPubMedCentralGoogle Scholar
  297. Zhang L, Schaner ME, Giacomini KM (1998) Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J Pharmacol Exp Ther 286:354–361PubMedGoogle Scholar
  298. Zhang W, Yu BN, He YJ, Fan L, Li Q, Liu ZQ et al (2006) Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta 373:99–103CrossRefGoogle Scholar
  299. Zhao G, Huang J, Xue K, Si L, Li G (2013) Enhanced intestinal absorption of etoposide by self-microemulsifying drug delivery systems: roles of P-glycoprotein and cytochrome P450 3A inhibition. Eur J Pharm Sci 50:429–439CrossRefPubMedPubMedCentralGoogle Scholar
  300. Zheng X, Ekins S, Raufman JP, Polli JE (2009) Computational models for drug inhibition of the human apical sodium-dependent bile acid transporter. Mol Pharm 6:1591–1603CrossRefPubMedPubMedCentralGoogle Scholar
  301. Zhou M, Xia L, Wang J (2007) Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos 35:1956–1962CrossRefPubMedPubMedCentralGoogle Scholar
  302. Ziegler TR, Fernandez-Estivariz C, Gu LH, Bazargan N, Umeakunne K, Wallace TM et al (2002) Distribution of the H+/peptide transporter PepT1 in human intestine: up-regulated expression in the colonic mucosa of patients with short-bowel syndrome. Am J Clin Nutr 75:922–930CrossRefPubMedPubMedCentralGoogle Scholar
  303. Zimmermann C, Gutmann H, Hruz P, Gutzwiller JP, Beglinger C, Drewe J (2005) Mapping of multidrug resistance gene 1 and multidrug resistance-associated protein isoform 1 to 5 mRNA expression along the human intestinal tract. Drug Metab Dispos 33:219–224CrossRefPubMedPubMedCentralGoogle Scholar
  304. Zolk O, Fromm MF (2011) Transporter-mediated drug uptake and efflux: important determinants of adverse drug reactions. Clin Pharmacol Ther 89:798–805CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Shanghai Institute of Materia MedicaShanghaiChina
  2. 2.Novartis Institutes for Biomedical ResearchEast HanoverUSA
  3. 3.University of Chinese Academy of ScienceBeijingChina

Personalised recommendations