Intestinal Absorption of Drugs Mediated by Drug Transporters: Mechanisms and Regulation

Drug Metabolism And Pharmacokinetics

Volumn 18, Issue 1, 2003, Pages 1-15

  Katsura, Toshiya ^a   Inui, Ken Ichi ^a  

^a KYOTO UNIVERSITY HOSPITAL   (Japan)

Author keywords

basolateral membrane; brush border membrane; Caco 2; intestinal absorption; transporter

Indexed keywords

EID: 85009583484     PISSN: 13474367     EISSN: 18800920     Source Type: Journal    
DOI: 10.2133/dmpk.18.1     Document Type: Review

References (127)

1. Okano, T., Inui, K., Maegawa, H., Takano, M. and Hori, R.: H+ coupled uphill transport of aminocephalosporins via the dipeptide transport system in rabbit intestinal brush-border membranes. J. Biol. Chem., 261: 14130-14134 (1986).
2. Murer, H., Gmaj, P., Steiger, B. and Hagenbuch, B.: Transport studies with renal proximal tubular and small intestinal brush border and basolateral membrane vesicles: vesicle heterogeneity, coexistence of transport system. Methods Enzymol., 172: 346-364 (1989).
3. Inui, K., Takano, M. and Hori, R.: Organic cation transport in the renal brush-border and basolateral membranes. In Hatano, M. (ed.): Nephrology, Tokyo, Springer-Verlag Tokyo, 1991, pp. 1391-1398.
4. Hidalgo, I. J., Raub, T. J. and Borchardt, R. T.: Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology, 96: 736-749 (1989).
5. Inui, K., Yamamoto, M. and Saito, H.: Transepithelial transport of oral cephalosporins by monolayers of intestinal epithelial cell line Caco-2: specific transport systems in apical and basolateral membranes. J. Pharmacol. Exp. Ther., 261: 195-201 (1992).
6. Artursson, P. and Borchardt, R. T.: Intestinal drug absorption and metabolism in cell culture: Caco-2 and beyond. Pharm. Res., 14: 1655-1658 (1997).
7. Lennernäs, H.: Human intestinal permeability. J. Pharm. Sci., 87: 403-410 (1998).
8. Artursson, P., Palm, K. and Luthman, K.: Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv. Drug Deliv. Rev., 46: 27-43 (2001).
9. Hediger, M. A., Coady, M. J., Ikeda, T. S. and Wright, E. M.: Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. Nature, 330: 379-381 (1987).
10. Romero, M. F., Kanai, Y., Gunshin, H. and Hediger, M. A.: Expression cloning using Xenopus laevis oocytes. Methods Enzymol., 296: 17-52 (1998).
11. Fei, Y.-J., Kanai, Y., Nussberger, S., Ganapathy, V., Leibach, F. H., Romero, M. F., Singh, S. K., Boron, W. F. and Hediger, M. A.: Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature, 368: 563-566 (1994).
12. Gründemann, D., Gorboulev, V., Gambaryan, S., Veyhl, M. and Koepsell, H.: Drug excretion mediated by a new prototype of polyspecific transporter. Nature, 372: 549-552 (1994).
13. Jacquemin, E., Hagenbuch, B., Stieger, B., Wolkoff, A. W. and Meier, P. J.: Expression cloning of a rat liver Na+-independent organic anion transporter. Proc. Natl. Acad. Sci. USA, 91: 133-137 (1994).
14. Inui, K. and Okuda, M.: Cellular and molecular mechanisms of renal tubular secretion of organic anions and cations. Clin. Exper. Nephrol., 2: 100-108 (1998).
15. Inui, K., Masuda, S. and Saito, H.: Cellular and molecular aspects of drug transport in the kidney. Kidney Int., 58: 944-958 (2000).
16. Tamai, I. and Tsuji, A.: Transporter-mediated permeation of drugs across blood-brain barrier. J. Pharm. Sci., 89: 1371-1388 (2000).
17. Burckhardt, G. and Wolff, N. A.: Structure of renal organic anion and cation transporters. Am. J. Physiol. Renal Physiol., 278: F853-F866 (2000).
18. Sekine, T., Cha, S. H. and Endou, H.: The multispecific organic anion transporter (OAT) family. Pflügers Arch., 440: 337-350 (2000).
19. Lee, V. H. L.: Membrane transporters. Eur. J. Pharm. Sci., 11: S41-S50 (2000).
20. Dresser, M. J., Leabman, M. K. and Giacomini, K. M.: Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J. Pharm. Sci., 90: 397-421 (2001).
21. Sweet, D. H., Bush, K. T. and Nigam, S. K.: The organic anion transporter family: from physiology to ontogeny and the clinic. Am. J. Physiol. Renal Physiol., 281: F197-F205 (2001).
22. Russel, F. G. M., Masereeuw, R. and van Aubel, R. A. M. H.: Molecular aspects of renal anionic drug transport. Annu. Rev. Physiol., 64: 563-594 (2002).
23. Meier, P. J. and Stieger, B.: Bile salt transporters. Annu. Rev. Physiol., 64: 635-661 (2002).
24. Kusuhara, H. and Sugiyama, Y.: Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney. J. Control. Release, 78: 43-54 (2002).
25. Mizuno, N. and Sugiyama, Y.: Drug transporters: Their role and importance in the selection and development of new drugs. Drug Metabol. Pharmacokin., 17: 93-108 (2002).
26. Tsuji, A.: Transporter-mediated drug interactions. Drug Metabol. Pharmacokin., 17: 253-274 (2002).
27. Liang, R., Fei, Y.-J., Prasad, P. D., Ramamoorthy, S., Han, H., Yang-Feng, T. L., Hediger, M. A., Ganapathy, V. and Leibach, F. H.: Human intestinal H+/peptide co-transporter. Cloning, functional expression, and chromosomal localization. J. Biol. Chem., 270: 6456-6463 (1995).
28. Saito, H., Okuda, M., Terada, T., Sasaki, S. and Inui, K.: Cloning and characterization of a rat H+/peptide co-transporter mediating absorption of β-lactam antibiotics in the intestine and kidney. J. Pharmacol. Exp. Ther., 275: 1631-1637 (1995).
29. Fei, Y.-J., Sugawara, M., Liu, J.-C., Li, H. W., Ganapathy, V., Ganapathy, M. E. and Leibach, F. H.: cDNA structure, genomic organization, and promoter analysis of the mouse intestinal peptide transporter PEPT1. Biochim. Biophys. Acta, 1492: 145-154 (2000).
30. Pan, Y., Wong, E. A., Bloomquist, J. R. and Webb, K. E., Jr.: Expression of a cloned ovine gastrointestinal peptide transporter (oPepT1) in Xenopus oocytes induces uptake of oligopeptides in vitro. J. Nutr., 131: 1264-1270 (2001).
31. Chen, H., Pan, Y., Wong, E. A., Bloomquist, J. R. and Webb, K. E., Jr.: Molecular cloning and functional expression of a chicken intestinal peptide transporter (cPepT1) in Xenopus oocytes and Chinese hamster ovary cells. J. Nutr., 132: 387-393 (2002).
32. Leibach, F. H. and Ganapathy, V.: Peptide transporters in the intestine and the kidney. Annu. Rev. Nutr., 16: 99-119 (1996).
33. Daniel, H.: Function and molecular structure of brush border membrane peptide/H+ symporters. J. Membrane Biol., 154: 197-203 (1996).
34. Adibi, S. A.: The oligopeptide transporter (Pept-1) in human intestine: biology and function. Gastroenterology, 113: 332-340 (1997).
35. Inui, K. and Terada, T.: Dipeptide transporters. In Amidon, G. L. and Sadée, W. (eds.): Membrane Transporters as Drug Targets, New York, Kluwer Academic/Plenum Publishers, 1999, pp. 269-288.
36. Yang, C. Y., Dantzig, A. H. and Pidgeon, C.: Intestinal peptide transport systems and oral drug availability. Pharm. Res., 16: 1331-1343 (1999).
37. Lee, V. H. L., Chu, C., Mahlin, E. D., Basu, S. K., Ann, D. K., Bolger, M. B., Haworth, I. S., Yeung, A. K., Wu, S. K., Hamm-Alvarez, S. and Okamoto, C. T.: Biopharmaceutics of transmucosal peptide and protein drug administration: role of transport mechanisms with a focus on the involvement of PepT1. J. Control. Release, 62: 129-140 (1999).
38. Meredith, D. and Boyd, C. A. R.: Structure and function of eukaryotic peptide transporters. Cell. Mol. Life Sci., 57: 754-778 (2000).
39. Brodin, B., Nielsen, C. U., Steffansen, B. and Frokjer, S.: Transport of peptidomimetic drugs by the intestinal di/tri-peptide transporter, PepT1. Pharmacol. Toxicol., 90: 285-296 (2002).
40. Rubio-Aliaga, I. and Daniel, H.: Mammalian peptide transporters as targets for drug delivery. Trends Pharmacol. Sci., 23: 434-440 (2002).
41. Surendran, N., Covitz, K.-M. Y., Han, H., Sadee, W., Oh, D.-M., Amidon, G. L., Williamson, R. M., Bigge, C. F. and Stewart, B. H.: Evidence for overlapping substrate specificity between large neutral amino acid (LNAA) and dipeptide (hPEPT1) transporters for PD 158473, an NMDA antagonist. Pharm. Res., 16: 391-395 (1999).
42. Watanabe, K., Sawano, T., Terada, K., Endo, T., Sakata, M. and Sato, J.: Studies on intestinal absorption of sulpiride (1): carrier-mediated uptake of sulpiride in the human intestinal cell line Caco-2. Biol. Pharm. Bull., 25: 885-890 (2002).
43. Tamai, I., Nakanishi, T., Nakahara, H., Sai, Y., Ganapathy, V., Leibach, F. H. and Tsuji, A.: Improvement of L-dopa absorption by dipeptidyl derivation, utilizing peptide transporter PepT1. J. Pharm. Sci., 87: 1542-1546 (1998).
44. Weiss, W. J., Mikels, S. M., Petersen, P. J., Jacobus, N. V., Bitha, P., Lin, Y.-I. and Testa, R. T.: In vivo activities of peptidic prodrugs of novel aminomethyl tetrahydrofuranyl-1 β-methylcarbapenems. Antimicrob. Agents Chemother., 43: 460-464 (1999).
45. Ezra, A., Hoffman, A., Breuer, E., Alferiev, I. S., Mönkkönen, J., El Hanany-Rozen, N., Weiss, G., Stepensky, D., Gati, I., Cohen, H., Törmälehto, S., Amidon, G.L. and Golomb, G.: A peptide prodrug approach for improving bisphosphonate oral absorption. J. Med. Chem., 43: 3641-3652 (2000).
46. Friedrichsen, G. M., Jakobsen, P., Taub, M. and Begtrup, M.: Application of enzymatically stable dipeptides for enhancement of intestinal permeability. Synthesis and in vitro evaluation of dipeptide-coupled compounds. Bioorg. Med. Chem., 9: 2625-2632 (2001).
47. Nielsen, C. U., Supuran, C. T., Scozzafava, A., Frokjer, S., Steffansen, B. and Brodin, B.: Transport characteristics of L-carnosine and the anticancer derivative 4-toluenesulfonylureido-carnosine in a human epithelial cell line. Pharm. Res., 19: 1337-1344 (2002).
48. Temple, C. S., Stewart, A. K., Meredith, D., Lister, N. A., Morgan, K. M., Collier, I. D., Vaughan-Jones, R. D., Boyd, C. A. R., Bailey, P. D. and Bronk, J. R.: Peptide mimics as substrates for the intestinal peptide transporter. J. Biol. Chem., 273: 20-22 (1998).
49. Döring, F., Walter, J., Will, J., Föcking, M., Boll, M., Amasheh, S., Clauss, W. and Daniel, H.: Delta-aminolevulinic acid transport by intestinal and renal peptide transporters and its physiological and clinical implications. J. Clin. Invest., 101: 2761-2767 (1998).
50. Döring, F., Will, J., Amasheh, S., Clauss, W., Ahlbrecht, H. and Daniel, H.: Minimal molecular determinants of substrates for recognition by the intestinal peptide transporter. J. Biol. Chem., 273: 23211-23218 (1998).
51. Börner, V., Fei, Y.-J., Hartrodt, B., Ganapathy, V., Leibach, F. H., Neubert, K. and Brandsch, M.: Transport of amino acid aryl amides by the intestinal H+/peptide cotransport system, PEPT1. Eur. J. Biochem., 255: 698-702 (1998).
52. Ganapathy, M. E., Huang, W., Wang, H., Ganapathy, V. and Leibach, F. H.: Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem. Biophys. Res. Commun., 246: 470-475 (1998).
53. Balimane, P. V., Tamai, I., Guo, A., Nakanishi, T., Kitada, H., Leibach, F. H., Tsuji, A. and Sinko, P. J.: Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem. Biophys. Res. Commun., 250: 246-251 (1998).
54. Han, H. K., Oh, D.-M. and Amidon, G. L.: Cellular uptake mechanism of amino acid ester prodrugs in Caco-2/hPEPT1 cells overexpressing a human peptide transporter. Pharm. Res., 15: 1382-1386 (1998).
55. Sugawara, M., Huang, W., Fei, Y.-J., Leibach, F. H., Ganapathy, V. and Ganapathy, M. E.: Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J. Pharm. Sci., 89: 781-789 (2000).
56. Sawada, K., Terada, T., Saito, H., Hashimoto, Y. and Inui, K.: Recognition of L-amino acid ester compounds by rat peptide transporters PEPT1 and PEPT2. J. Pharmacol. Exp. Ther., 291: 705-709 (1999).
57. Bailey, P. D., Boyd, C. A. R., Bronk, J. R., Collier, I. D., Meredith, D., Morgan, K. M. and Temple, C. S.: How to make drugs orally active: a substrate template for peptide transporter PepT1. Angew. Chem. Int. Ed., 39: 505-508 (2000).
58. Terada, T., Sawada, K., Saito, H., Hashimoto, Y. and Inui, K.: Functional characteristics of basolateral peptide transporter in the human intestinal cell line Caco-2. Am. J. Physiol., 276: G1435-G1441 (1999).
59. Sawada, K., Terada, T., Saito, H. and Inui, K.: Distinct transport characteristics of basolateral peptide transporters between MDCK and Caco-2 cells. Pflügers Arch., 443: 31-37 (2001).
60. Shu, C., Shen, H., Hopfer, U. and Smith, D. E.: Mechanism of intestinal absorption and renal reabsorption of an orally active ace inhibitor: uptake and transport of fosinopril in cell cultures. Drug. Metab. Dispos., 29: 1307-1315 (2001).
61. Irie, M., Terada, T., Sawada, K., Saito, H. and Inui, K.: Recognition and transport characteristics of non-peptidic compounds by basolateral peptide transporter in Caco-2 cells. J. Pharmacol. Exp. Ther., 298: 711-717 (2001).
62. Shepherd, E. J., Lister, N., Affleck, J. A., Bronk, J. R., Kellett, G. L., Collier, I. D., Bailey, P. D. and Boyd, C. A. R.: Identification of a candidate membrane protein for the basolateral peptide transporter of rat small intestine. Biochem. Biophys. Res. Commun., 296: 918-922 (2002).
63. Koepsell, H.: Organic cation transporters in intestine, kidney, liver, and brain. Annu. Rev. Physiol., 60: 243-266 (1998).
64. Zhang, L., Brett, C. M. and Giacomini, K. M.: Role of organic cation transporters in drug absorption and elimination. Annu. Rev. Pharmacol. Toxicol., 38: 431-460 (1998).
65. Okuda, M., Saito, H., Urakami, Y., Takano, M. and Inui, K.: cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem. Biophys. Res. Commun., 224: 500-507 (1996).
66. Gorboulev, V., Ulzheimer, J. C., Akhoundova, A., Ulzheimer-Teuber, I., Karbach, U., Quester, S., Baumann, C., Lang, F., Busch, A. E. and Koepsell, H.: Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol., 16: 871-881 (1997).
67. Jonker, J. W., Wagenaar, E., Mol, C. A. A. M., Buitelaar, M., Koepsell, H., Smit, J. W. and Schinkel, A. H.: 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: 5471-5477 (2001).
68. Zwart, R., Verhaagh, S., Buitelaar, M., Popp-Snijders, C. and Barlow, D. P.: Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol. Cell. Biol., 21: 4188-4196 (2001).
69. Wang, D.-S., Jonker, J. W., Kato, Y., Kusuhara, H., Schinkel, A. H. and Sugiyama, Y.: Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Exp. Ther., 302: 510-515 (2002).
70. Zhang, L., Gorset, W., Dresser, M. J. and Giacomini, K. M.: The interaction of n-tetraalkylammonium compounds with a human organic cation transporter, hOCT1. J. Pharmacol. Exp. Ther., 288: 1192-1198 (1999).
71. Bleasby, K., Chauhan, S. and Brown, C. D. A.: Characterization of MPP+ secretion across human intestinal Caco-2 cell monolayers: role of P-glycoprotein and a novel Na+-dependent organic cation transport mechanism. Br. J. Pharmacol., 129: 619-625 (2000).
72. Martel. F., Gründemann, D., Calhau, C. and Schömig, E.: Apical uptake of organic cations by human intestinal Caco-2 cells: putative involvement of ASF transporters. Naunyn-Schmiedeberg's Arch. Pharmacol., 363: 40-49 (2001).
73. Hayer-Zillgen, M., Brüss, M. and Bönisch, H.: Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br. J. Pharmacol., 136: 829-836 (2002).
74. Mizuuchi, H., Katsura, T., Saito, H., Hashimoto, Y. and Inui, K.: Transport characteristics of diphenhydramine in human intestinal epithelial Caco-2 cells: contribution of pH-dependent transport system. J. Pharmacol. Exp. Ther., 290: 388-392 (1999).
75. Mizuuchi, H., Katsura, T., Ashida, K., Hashimoto, Y. and Inui, K.: Diphenhydramine transport by pH-dependent tertiary amine transport system in Caco-2 cells. Am. J. Physiol. Gastrointest. Liver Physiol., 278: G563-G569 (2000).
76. Katsura, T., Mizuuchi, H., Hashimoto, Y. and Inui, K.: Transport of procainamide via H+/tertiary amine antiport system in rabbit intestinal brush-border membrane. Am. J. Physiol. Gastrointest. Liver Physiol., 279: G799-G805 (2000).
77. Miyamoto, Y., Ganapathy, V. and Leibach, F. H.: Transport of guanidine in rabbit intestinal brush-border membrane vesicles. Am. J. Physiol., 255: G85-G92 (1988).
78. Laforenza, U., Orsenigo, M. N. and Rindi, G.: A thiamine/H+ antiport mechanism for thiamine entry into brush-border membrane vesicles from rat small intestine. J. Membrane Biol., 161: 151-161 (1998).
79. Tamai, I., Saheki, A., Saitoh, R., Sai, Y., Yamada, I. and Tsuji, A.: Nonlinear intestinal absorption of 5-hydroxytryptamine receptor antagonist caused by absorptive and secretory transporters. J. Pharmacol. Exp. Ther., 283: 108-115 (1997).
80. Fukada, A., Saito, H. and Inui, K.: Transport mechanisms of nicotine across the human intestinal epithelial cell line Caco-2. J. Pharmacol. Exp. Ther., 302: 532-538 (2002).
81. Garcia, C. K., Goldstein, J. L., Pathak, R. K., Anderson, R. G. and Brown, M. S.: Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle. Cell, 76: 865-873 (1994).
82. Halestrap, A. P. and Price, N. T.: The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem. J., 343: 281-299 (1999).
83. Tamai, I., Takanaga, H., Maeda, H., Ogihara, T., Yoneda, M. and Tsuji, A.: Proton-cotransport of pravastatin across intestinal brush-border membrane. Pharm. Res., 12: 1727-1732 (1995).
84. Wu, X., Whitfield, L. R. and Stewart, B. H.: Atorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and the proton-monocarboxylic acid co-transporter. Pharm. Res., 17: 209-215 (2000).
85. Tamai, I., Sai, Y., Ono, A., Kido, Y., Yabuuchi, H., Takanaga, H., Satoh, E., Ogihara, T., Amano, O., Izeki, S. and Tsuji, A.: Immunohistochemical and functional characterization of pH-dependent intestinal absorption of weak organic acids by the monocarboxylic acid transporter MCT1. J. Pharm. Pharmacol., 51: 1113-1121 (1999).
86. Takagi, M., Taki, Y., Sakane, T., Nadai, T., Sezaki, H., Oku, N. and Yamashita, S.: A new interpretation of salicylic acid transport across the lipid bilayer: implications of pH-dependent but not carrier-mediated absorption from the gastrointestinal tract. J. Pharmacol. Exp. Ther., 285: 1175-1180 (1998).
87. Okamura, A., Emoto, A., Koyabu, N., Ohtani, H. and Sawada, Y.: Transport and uptake of nateglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1. Br. J. Pharmacol., 137: 391-399 (2002).
88. Sekine, T., Watanabe, N., Hosoyamada, M., Kanai, Y. and Endou, H.: Expression cloning and characterization of a novel multispecific organic anion transporter. J. Biol. Chem., 272: 18526-18529 (1997).
89. Walters, H. C., Craddock, A. L., Fusegawa, H., Willingham, M. C. and Dawson, P. A.: Expression, transport properties, and chromosomal location of organic anion transporter subtype 3. Am. J. Physiol. Gastrointest. Liver Physiol., 279: G1188-G1200 (2000).
90. Tamai, I., Nezu, J., Uchino, H., Sai, Y., Oku, A., Shimane, M. and Tsuji, A.: Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem. Biophys. Res. Commun., 273: 251-260 (2000).
91. Kullak-Ublick, G. A., Ismair, M. G., Stieger, B., Landmann, L., Huber, R., Pizzagalli, F., Fattinger, K., Meier, P. J. and Hagenbuch, B.: Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology, 120: 525-533 (2001).
92. Dresser, G. K., Bailey, D. G., Leake, B. F., Schwarz, U. I., Dawson, P. A., Freeman, D. J. and Kim, R. B.: Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin. Pharmacol. Ther., 71: 11-20 (2002).
93. Cvetkovic, M., Leake, B., Fromm, M. F., Wilkinson, G. R. and Kim, R. B.: OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug. Metab. Dispos., 27: 866-871 (1999).
94. Suzuki, H. and Sugiyama, Y.: Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. Eur. J. Pharm. Sci., 12: 3-12 (2000).
95. Zhang, Y. and Benet, L. Z.: The gut as a barrier to drug absorption. Combined role of cytochrome P450 3A and P-glycoprotein. Clin. Pharmacokinet., 40: 159-168 (2001).
96. Wagner, D., Spahn-Langguth, H., Hanafy, A., Koggel, A. and Langguth, P.: Intestinal drug efflux: formulation and food effects. Adv. Drug Deliv. Rev., 50: S13-S31 (2001).
97. Pastor-Anglada, M., Felipe, A. and Casado, F. J.: Transport and mode of action of nucleoside derivatives used in chemical and antiviral therapies. Trends Pharmacol. Sci., 19: 424-430 (1998).
98. Chu, X.-Y., Sánchez-Castao, G. P., Higaki, K., Oh, D.-M., Hsu, C.-P. and Amidon, G. L.: Correlation between epithelial cell permeability of cephalexin and expression of intestinal oligopeptide transporter. J. Pharmacol. Exp. Ther., 299: 575-582 (2001).
99. Erickson, R. H., Gum, J. R., Jr., Lindstrom, M. M., McKean, D. and Kim, Y. S.: Regional expression and dietary regulation of rat small intestinal peptide and amino acid transporter mRNAs. Biochem. Biophys. Res. Commun., 216: 249-257 (1995).
100. Walker, D., Thwaites, D. T., Simmons, N. L., Gilbert, H. J. and Hirst, B. H. Substrate upregulation of the human small intestinal peptide transporter, hPepT1. J. Physiol. (Lond), 507: 697-706 (1998).
101. Thamotharan, M., Bawani, S. Z., Zhou, X. and Adibi, S. A.: Mechanism of dipeptide stimulation of its own transport in a human intestinal cell line. Proc. Assoc. Am. Physicians, 110: 361-368 (1998).
102. Shiraga, T., Miyamoto, K., Tanaka, H., Yamamoto, H., Taketani, Y., Morita, K., Tamai, I., Tsuji, A. and Takeda, E. Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/peptide transporter PepT1. Gastroenterology, 116: 354-362 (1999).
103. Ogihara, H., Suzuki, T., Nagamachi, Y., Inui, K. and Takata, K.: Peptide transporter in the rat small intestine: Ultrastructural localization and the effect of starvation and administration of amino acids. Histochem. J., 31: 169-174 (1999).
104. Thamotharan, M., Bawani, S. Z., Zhou, X. and Adibi, S. A.: Functional and molecular expression of intestinal oligopeptide transporter (Pept-1) after a brief fast. Metabolism, 48: 681-684 (1999).
105. Ihara, T., Tsujikawa, T., Fujiyama, Y. and Bamba, T.: Regulation of PepT1 peptide transporter expression in the rat small intestine under malnourished conditions. Digestion, 61: 59-67 (2000).
106. Pan, X., Terada, T., Irie, M., Saito, H. and Inui, K.: Diurnal rhythm of H+-peptide co-transporter in rat small intestine. Am. J. Physiol. Gastrointest. Liver Physiol., 283: G57-G64 (2002).
107. Fujita, T., Majikawa, Y., Umehisa, S., Okada, N., Yamamoto, A., Ganapathy, V. and Leibach, F. H.: s Receptor ligand-induced upregulation of the H+/peptide transporter PEPT1 in the human intestinal cell line Caco-2. Biochem. Biophys. Res. Commun., 261: 242-246 (1999).
108. Gangopadhyay, A., Thamotharan, M. and Adibi, S. A.: Regulation of oligopeptide transporter (Pept-1) in experimental diabetes. Am. J. Physiol. Gastrointest. Liver Physiol., 283: G133-G138 (2002).
109. Nielsen, C. U., Amstrup, J., Steffansen, B., Frokjaer, S. and Brodin, B.: Epidermal growth factor inhibits glycylsarcosine transport and hPepT1 expression in a human intestinal cell line. Am. J. Physiol. Gastrointest. Liver Physiol., 281: G191-G199 (2001).
110. Ashida, K., Katsura, T., Motohashi, H., Saito, H. and Inui, K.: Thyroid hormone regulates the activity and expression of the peptide transporter PEPT1 in Caco-2 cells. Am. J. Physiol. Gastrointest. Liver Physiol., 282: G617-G623 (2002).
111. Shu, H.-J., Takeda, H., Shinzawa, H., Takahashi, T. and Kawata, S.: Effect of lipopolysaccharide on Peptide transporter 1 expression in rat small intestine and its attenuation by dexamethasone. Digestion, 65: 21-29 (2002).
112. Thamotharan, M., Bawani, S. Z., Zhou, X. and Adibi, S. A.: Hormonal regulation of oligopeptide transporter Pept-1 in a human intestinal cell line. Am. J. Physiol., 276: C821-C826 (1999).
113. Berlioz, F., Maoret, J.-J., Paris, H., Laburthe, M., Farinotti, R. and Rozé, C.: a2-Adrenergic receptors stimulate oligopeptide transport in a human intestinal cell line. J. Pharmacol. Exp. Ther., 294: 466-472 (2000).
114. Buyse, M., Berlioz, F., Guilmeau, S., Tsocas, A., Voisin, T., Péranzi, G., Merlin, D., Laburthe, M., Lewin, M. J. M., Rozé, C. and Bado, A.: PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine. J. Clin. Invest., 108: 1483-1494 (2001).
115. Merlin, D., Steel, A., Gewirtz, A. T., Si-Tahar, M., Hediger, M. A. and Madara, J. L.: hPepT1-mediated epithelial transport of bacteria-derived chemotactic peptides enhances neutrophil-epithelial interactions. J. Clin. Invest., 102: 2011-2018 (1998).
116. Merlin, D., Si-Tahar, M., Sitaraman, S. V., Eastburn, K., Williams, I., Liu, X., Hediger, M. A. and Madara, J. L.: Colonic epithelial hPepT1 expression occurs in inflammatory bowel disease: transport of bacterial peptides influences expression of MHC class 1 molecules. Gastroenterology, 120: 1666-1679 (2001).
117. Ziegler, T. R., Fernández-Estávariz, C., Gu, L. H., Bazargan, N., Umeakunne, K., Wallace, T. M., Diaz, E. E., Rosado, K. E., Pascal, R. R., Galloway, J. R., Wilcox, J. N. and Leader, L. M.: Distribution of the H+/peptide transporter PepT1 in human intestine: upregulated expression in the colonic mucosa of patients with short-bowel syndrome. Am. J. Clin. Nutr., 75: 922-930 (2002).
118. Avissar, N. E., Ziegler, T. R., Wang, H. T., Gu, L. H., Miller, J. H., Iannoli, P., Leibach, F. H., Ganapathy, V. and Sax, H. C.: 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: 65-72 (2001).
119. Motohashi, H., Masuda, S., Katsura, T., Saito, H., Sakamoto, S., Uemoto, S., Tanaka, K. and Inui, K.: Expression of peptide transporter following intestinal transplantation in the rat. J. Surg. Res., 99: 294-300 (2001).
120. Thwaites, D. T., Kennedy, D. J., Raldua, D., Anderson, C. M. H., Mendoza, M. E., Bladen, C. L. and Simmons, N. L.: H+/dipeptide absorption across the human intestinal epithelium is controlled indirectly via a functional Na+/H+ exchanger. Gastroenterology, 122: 1322-1333 (2002).
121. Kennedy, D. J., Leibach, F. H., Ganapathy, V. and Thwaites, D. T.: Optimal absorptive transport of the dipeptide glycylsarcosine is dependent on functional Na+/H+ exchange activity. Pflügers Arch., 445: 139-146 (2002).
122. Wenzel, U., Kuntz, S. and Daniel, H.: Flavonoids with epidermal growth factor-receptor tyrosine kinase inhibitory activity stimulate PEPT1-mediated cefixime uptake into human intestinal epithelial cells. J. Pharmacol. Exp. Ther., 299: 351-357 (2001).
123. Wenzel, U., Kuntz, S., Diestel, S. and Daniel, H.: PEPT1-mediated cefixime uptake into human intestinal epithelial cells is increased by Ca2+ channel blockers. Antimicrob. Agents Chemother., 46: 1375-1380 (2002).
124. Westphal, J. F., Trouvin, J. H., Deslandes, A. and Carbon, C.: Nifedipine enhances amoxicillin absorption kinetics and bioavailability in humans. J. Pharmacol. Exp. Ther., 255: 312-317 (1990).
125. Duverne, C., Bouten, A., Deslandes, A., Westphal, J. F., Trouvin, J. H., Farinotti, R. and Carbon, C.: Modification of cefixime bioavailability by nifedipine in humans: involvement of the dipeptide carrier system. Antimicrob. Agents Chemother., 36: 2462-2467 (1992).
126. Harcouát, L., Lebrec, D., Rozé, C., Carbon, C. and Farinotti, R.: Increased intestinal absorption of cefixime by nifedipine in the rat intestinal perfusion model: evidence for a neural regulation. J. Pharmacol. Exp. Ther., 281: 738-745 (1997).
127. Berlioz, F., Julien, S., Tsocas, A., Chariot, J., Carbon, C., Farinotti, R. and Rozé, C.: Neural modulation of cephalexin intestinal absorption through the di-and tripeptide brush border transporter of rat jejunum in vivo. J. Pharmacol. Exp. Ther., 288: 1037-1044 (1999).