Skip to main content
Log in

Carrier-Mediated Intestinal Transport of Drugs

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Recent advances in the field of carrier-mediated intestinal absorption of of amino acids, oligopeptides, monosaccharides, monocarboxylic acids, phosphate, bile acids and several water-soluble vitamins across brush-border and basolateral membranes are summarized. An understanding of the molecular and functional characteristics of the intestinal membrane transporters will be helpful in the utilization of these transporters for the enhanced oral delivery of poorly absorbed drugs. Some successful examples of the synthesis of prodrugs recognized by the targeted transporters are described. Functional expression of the multidrug resistance gene product, P-glycoprotein, as a primary active transporter in the intestinal brush-border membrane leads to net secretion of some drugs such as anticancer agents in the blood-to-luminal direction, serving as a secretory detoxifying mechanism and as a part of the absorption barrier in the intestine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. T. Hoshi. Proton-coupled transport of organic solutes in animal cell membranes and its relation to Na+ transport. Japn. J. Phys. 35:179–191 (1985).

    Google Scholar 

  2. M. Lucus. Determination of acid surface pH in vivo in rat proximal jejunum. Gut 24:734–739 (1983).

    Google Scholar 

  3. H. Murer, U. Hopfer, and R. Kinne. Sodium/proton antiport in brush-border membrane vesicles isolated from rat small intestine and kidney. Biochem. J. 154:597–604 (1976).

    Google Scholar 

  4. V. Ganapathy, M. Brandsch, and F. H. Leibach. Intestinal transport of amino acids and peptides. In L. R. Johnson (ed.), Physiology of the gastrointestinal tract, third ed., Raven Press, New York, N. Y., pp.1773–1794 (1994).

    Google Scholar 

  5. H. N. Christensen. Distinguishing amino acid transport systems of a given cell or tissue. Meth. Enzymol. 173:576–616 (1989).

    Google Scholar 

  6. L. K. Munck and B. G. Munck. Chloride-dependence of amino acid transport in rabbit ileum. Biochim. Biophys. Acta 1027:17–20 (1990).

    Google Scholar 

  7. Y. Miyamoto, C. Tirrupathi, V. Ganapathy, and F. H. Leibach. Active transport of taurine in rabbit jejunal brush-border membrane vesicles. Am. J. Physiol. 257:G65–G72 (1989).

    Google Scholar 

  8. D. T. Thwaites, G. T. A. McEwan, B. H. Hirst, and N. L. Simmons. H+-coupled α-methylaminoisobutyric acid transport in human intestinal Caco-2 cells. Biochim. Biophys. Acta 1234:111–118 (1995).

    Google Scholar 

  9. M. A. Hediger, Y. Kanai, G. You, and S. Nussberger. Mammalian ion-coupled solute transporters. J. Physiol. 482, 7S–17S (1995).

    Google Scholar 

  10. B. H. Stewart, A. R. Kugler, P. R. Thompson, and N. Bockbrader. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm. Res. 10:276–281 (1993).

    Google Scholar 

  11. G. L. Amidon, A. E. Merfeld, and J. B. Dressman. Concentration and pH dependency of α-methyldopa absorption in rat intestine. J. Pharm. Pharmacol. 38:363–368 (1986).

    Google Scholar 

  12. M. Hu and R. T. Borchardt. Mechanism of L-α-methyldopa transport through a monolayer of polarized human intestinal epithelial cells (Caco-2). Pharm. Res. 7:1313–1319 (1990).

    Google Scholar 

  13. H. Shindo, T. Komai, and K. Kawai. Studies on the metabolism of D-and L-isomers of 3,4-dihydroxyphenylalanine (DOPA). V. Mechanism of intestinal absorption of D-and L-DOPA-14C in rats. Chem. Pharm. Bull (Tokyo). 21:2031–2038 (1973).

    Google Scholar 

  14. T. Cercos-Fortea, A. Polache, A. Nacher, E. Cejudo-Ferragud, V. G. Casabo, and M. Merino. Influence of leucine on intestinal baclofen absorption as a model compound of neutral α-amino acids. Biopharm. Drug Dispos. 16:563–577 (1995).

    Google Scholar 

  15. D. T. Thwaites, G. Armstrong, B. H. Hirst, and N. L. Simmons. D-cycloserine transport in human intestinal epithelial (Caco-2) cells mediated by a H+-coupled amino acid transporter. Brit. J. Pharmacol. 115:761–766 (1995).

    Google Scholar 

  16. V. Ganapathy and F. H. Leibach. Is intestinal peptide transport energized by a proton gradient? Am. J. Physiol. 249:G153–G160 (1985).

    Google Scholar 

  17. H. Minami, E. L. Morse, and S. A. Adibi. Characteristics and mechanism of glutamine-dipeptide absorption in human intestine. Gastroenterology 103:3–11 (1992).

    Google Scholar 

  18. Y.-J. Fei, Y. Kanai, S. Nussberger, V. Ganapathy, F. H. Leibach, M. F. Romero, S. K. Singh, W. F. Boron, and M. A. Hediger. Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature 368:563–566 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. R. Liang, Y.-J. Fei, P. D. Presad, S. Ramamoorthy, H. Han, T. L. Yang-Feng, M. A. Hediger, V. Ganapathy, and F. H. Leibach. Human intestinal H+/peptide cotransporter. Cloning, functional expression, and chromosomal localization. J. Biol. Chem. 270:6456–6463 (1995).

    Google Scholar 

  20. K. Miyamoto, T. Shiraga, H. Yamamoto, H. Haga, Y. Taketani, K. Morita, I. Tamai, Y. Sai, A. Tsuji, and E. Takeda. Sequence, tissue distribution and developmental changes in rat intestinal oligopeptide transporter. Biochem. Biophys. Acta, 1305:34–38(1996).

    Google Scholar 

  21. I. Tamai, K. Hayashi, T. Terao, Y. Sai, T. Shiraga, K. Miyamoto, E. Takeda, H. Higashida, and A. Tsuji. H+ coupled transport of β-lactam antibiotics mediated by oligopeptide transporter, PepT1, cloned from rat small intestine. submitted.

  22. J. Dyer, R. B. Beechey, J.-P. Gorvel, R. T. Smith, R. Wootton, and S. P. Shirazi-Beechey. Glycyl-L-proline transport in rabbit enterocyte basolateral membrane vesicles. Biochem. J. 269:565–571 (1990).

    Google Scholar 

  23. D. T. Thwaites, C. D. A. Brown, B. H. Hirst, and N. L. Simmons. Transepithelial glycylsarcosine transport in intestinal Caco-2 cells mediated by expression of H+-coupled carriers at both apical and basal membranes. J. Biol. Chem. 268:7640–7642 (1993).

    Google Scholar 

  24. W. Liu, R. Liang, S. Ramamoorthy, Y-J. Fei, M. E. Ganapathy, M. A. Hediger, V. Ganapathy, and F. H. Leibach. Molecular cloning of PEPT 2, a new member of the H+/peptide cotransport family, from human kidney. Biochim. Biophys. Acta 1235:461–466 (1995).

    Google Scholar 

  25. A. Tsuji. Intestinal absorption of β-lactam antibiotics; In M. D. Taylor and G. L. Amidon (eds.), Peptide-based drug design, American Chemical Society, Washington, DC, pp. 299–316 (1995).

    Google Scholar 

  26. T. Okano, K. Inui, H. Maegawa, M. Takano, and R. Hori. H+ copuled uphill transport of aminocephalosporins via the dipeptide transport system in rabbit intestinal brush-border membranes. J. Biol. Chem. 261:14130–14134 (1986).

    Google Scholar 

  27. K. Inui, M. Miyamoto, and H. Saito. 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).

    Google Scholar 

  28. I. Tamai, N. Tomizawa, A. Kadowaki, T. Terasaki, K. Nakayama, H. Higashida, and A. Tsuji. Functional expression of intestinal depeptide/β-lactam antibiotic transporter in Xenopus laevis oocytes. Biochem. Pharmacol. 48:881–888 (1994).

    Google Scholar 

  29. I. Tamai, N. Tomizawa, T. Takeuchi, K. Nakayama, H. Higashida, and A. Tsuji. Functional expression of transporter for β-lactam antibiotics and dipeptides in Xenopus laevis oocytes injected with messenger RNA from human, rat and rabbit small intestines. J. Pharmacol. Exp. Ther. 273:26–31 (1995).

    Google Scholar 

  30. M. Boll, D. Markovich, W.-M. Weber, H. Korter, H. Daniel, and H. Murer. Expression cloning of a cDNA from rabbit small intestine related to proton-coupled transport of peptides, β-lactam antibiotics and ACE-inhibitors. Pflugers-Arch. 429:146–149 (1994).

    Google Scholar 

  31. G. L. Amidon and H. J. Lee. Absorption of peptide and peptidomimetic drugs. Annu. Rev. Pharmacol. Toxicol. 34:321–341 (1994).

    Google Scholar 

  32. S. Yee and G. L. Amidon. Oral absorption of angiotensin-converting enzyme inhibitors and peptide prodrugs; In M. D. Taylor and G. L. Amidon (eds.), Peptide-based drug design, American Chemical Society, Washington, DC, pp. 299–316. (1995).

    Google Scholar 

  33. W. Kramer, F. Girbig, U. Gutjahr, H. W. Kleemann, I. Leipe, H. Urbach, and A. Wagner. Interaction of renin inhibitors with the intestinal uptake system for oligopeptides and β-lactam antibiotics. Biochim. Biophys. Acta 1027:25–30 (1990).

    Google Scholar 

  34. N. Hashimoto, T. Fujioka, T. Toyoda, N. Muranishi, and K. Hirano. Renin inhibitor: transport mechanism in rat small intestinal brush-border membrane vesicles. Pharm. Res. 11:1448–1451 (1994).

    Google Scholar 

  35. M. Takano, Y. Tomita, T. Katsura, M. Yasuhara, K. Inui, and R. Hori. Bestatine trasnport in rabbit intestinal brush-border membrane vesicles. Biochem. Pharmacol. 47:1089–1090 (1994).

    Google Scholar 

  36. E. Walter, T. Kissel, M. Reers, G. Dickneite, D. Hofmann, and W. Stuber. Transepithelial properties of peptidomimetic thrombin inhibitors in monolayers of a human intestinal cell line (Caco-2) and their correlation to in vivo data. Pharm. Res. 12:360–365 (1995).

    Google Scholar 

  37. A. Tsuji, I. Tamai, M. Nakanishi, and G. L. Amidon, Mechanism of absorption of the dipeptide α-methyldopa-phe in the intestinal brush-border membrane vesicles. Pharm. Res. 7:308–309 (1990).

    Google Scholar 

  38. J. P. F. Bai. pGlu-L-dopa-pro: A tripeptide prodrug targeting the intestinal peptide transporter for absorption and tissue enzymes for conversion. Pharm. Res. 12:1101–1104 (1995).

    Google Scholar 

  39. J. R. Pappenheimer, and J. M. Madara. Role of active transport in regulation of junctional permeability and paracellular absorption of nutrients by intestinal epithelia. In H. Ussing (ed.), Transport in leaky epithelial, Copenhagen, Munksgaard (1993).

    Google Scholar 

  40. M. A. Hediger, M. J. Coady, T. S. Ikeda, and E. M. Wright. Expression cloning and cDNA sequencing of the Na+/glucose cotransporte. Nature 330:379–381 (1987).

    Google Scholar 

  41. M. A. Hediger and D. B. Rhoads. Molecular physiology of sodium-glucose cotransporters. Physiol. Rev. 74:993–1026 (1994).

    Google Scholar 

  42. W.-S. Lee, Y. Kanai, R. G. Wells, and M. A. Hediger. The high affinity Na+/glucose cotransporter. Re-evaluation of function and distribution of expression. J. Biol. Chem. 269:12032–12039 (1994).

    Google Scholar 

  43. T. Kayano, C. F. Burant, H. Fukumoto, G. W. Gould, Y-S. Fan,, R. L. Eddy, M. G. Byers, T. B. Shoes, S. Seino, and G. I. Bell. Human facilitative glucose transporters. J. Biol. Chem. 265:13276–13282 (1990).

    Google Scholar 

  44. E. B. Rand, A. M. Depaoli, N. O. Davidson, G. I. Bell, and C. F. Burant. Sequence, tissue distribution, and functional characterization of the rat fructose transporter GLUT5. Am. J. Physiol. 264:G1169–1176 (1993).

    Google Scholar 

  45. K. Miyamoto, S. Tatsumi, A. Morimoto, H. Minami, H. Yamamoto, K. Sone, Y. Taketani, Y. Nakabou, T. Oka, and E. Takeda. Characterizastion of the rabbit intestinal fructose transporter (GLUT5). Biochem. J. 303:877–883 (1994).

    Google Scholar 

  46. H. Fukumoto, S. Seino, H. Imura, Y. Seino, R. L. Eddy, Y. Fukushima, M. G. Byers, T. B. Shows, and G. I. Bell. Sequence, tissue distribution, and chromosomal localization of mRNA encoding a human glucose transporter-like protein. Proc. Natl. Acad. Sci. USA 85:5434–5438 (1988).

    Google Scholar 

  47. G. W. Gould, H. M. Thomas, T. J. Jess, and G. I. Bell. Expression of human glucose transporters in Xenopus Oocytes: kinetic characterization and substrate specificities of the erythrocyte, liver, and brain isoforms. Biochemistry 30:5139–5145 (1991).

    Google Scholar 

  48. B. Thorens, Z-Q. Cheng, D. Brown, and H. F. Lodish. Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells. Am. J. Physiol. 259:C279–285 (1990).

    Google Scholar 

  49. T. Mizuma, K. Ohta, M. Hayashi, and S. Awazu. Intestinal active absorption of sugar-conjugated compounds by glucose transport system: implication of improvement of poorly absorbable drugs. Biochem. Pharmacol. 43:2037–2039 (1992).

    Google Scholar 

  50. T. Mizuma, K. Ohta, and S. Awazu. The β-anomeric and glucose perferences of glucose transport carrier for intestinal active absorption of monosaccharide conjugates. Biochim. Biophys. Acta 1200:117–122 (1994).

    Google Scholar 

  51. T. Mizuma, N. Sakai, and S. Awazu. Na+-Dependent transport of aminopeptidase-resistant sugar-coupled tripeptides in rat intestine. Biochem. Biophys. Res. Commun. 203:1412–1416 (1994).

    Google Scholar 

  52. M., Haga, K. Saito, T. Shimaya, Y. Maezawa, Y. Kato, and S. W. Kim. Hypoglycemic effect of intestinally administered monosaccharide-modified insulin derivatives in rats. Chem. Pharm. Bull. 38:1983–1986 (1990).

    Google Scholar 

  53. G. Rechkemmer. Transport of weak electrolytes. In V. Schultz, Handbook of Physiology, American Physiological Society, Bethesda, MD, pp. 371–388 (1991).

    Google Scholar 

  54. M. L. Hougerle and D. Winne. Drug absorption by the rat jejunum perfused in situ. Dissociation from the pH-partition theory and role of microclimate-pH and unstirred layer. Naunyn-Schmiedebergs Arch Pharmacol. 322:249–255 (1983).

    Google Scholar 

  55. C. Tiruppathi, D. F. Balkovetz, V. Ganapathy, Y. Miyamoto, and F. H. Leibach. A proton gradient, not a sodium gradient, is the driving force for active transport of lactate in rabbit intestinal brush-border membrane vesicles. Biochem. J. 256:219–223 (1988).

    Google Scholar 

  56. M. Bugaut. Occurrence, absorption and metabolism of short chain fatty acids in the digestive tract of mammals. Comp. Biochem. Physiol. 86B:439–472 (1987).

    Google Scholar 

  57. A. Tsuji, M. T. Simanjuntak, I. Tamai, and T. Terasaki. pH-Dependent intestinal transport of monocarboxylic acids: carriermediated and H+-cotransport mechanism versus pH-partition hypothesis. J. Pharm. Sci. 79:1123–1124 (1990).

    Google Scholar 

  58. M. Dohgen, H. Hayashi, T. Yajima, and T. Suzuki. Stimulation of bicarbonate secretion by luminal short-chain fatty acids in the rat and human colon in vivo. Japn. J. Physiol. 44:519–531 (1994).

    Google Scholar 

  59. E. Titus and G. A. Aheam. Transintestinal acetate transport in a herbivorous teleost: anion exchange at the basolateral membrane. J. Exp. Biol. 156:41–61 (1991).

    Google Scholar 

  60. M. T. Simanjuntak, T. Terasaki, I. Tamai, and A. Tsuji. Participation of monocarboxylic anion and bicarbonate exchange system for the transport of acetic acid and monocarboxylic acid drugs in the small intestinal brush-border membrane vesicles. J. Pharmacobio-Dyn. 14:501–508 (1991).

    Google Scholar 

  61. J. M. Harig, K. H. Soergel, J. A. Barry, and K. Ramaswamy. Transport of propionate by ileal brush-border membrane vesicles. Am. J. Physiol. 260:G776–782 (1991).

    Google Scholar 

  62. R. C. Poole and A. P. Halestrap. N-Terminal protein sequence analysis of the rabbit erythrocyte lactate transporter suggests identity with the cloned mono-carboxylate transport protein MCT1. Biochem. J. 303:755–759 (1994).

    Google Scholar 

  63. C-K. Garcia, J. L. Goldstein, R. K. Pathak, R. G. W. Anderson, and M. S. Brown. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the cori cycle. Cell 76:865–873 (1994).

    Google Scholar 

  64. I. Tamai, H. Takanaga, H. Maeda, Y. Sai, T. Ogihara, H. Higashida, and A. Tsuji. Participation of a proton-cotransporter, MCT1 in the intestinal transport mechanism for monocarboxylic acids. Biochem. Biophys. Res. Commun. 214:482–489 (1995).

    Google Scholar 

  65. H. Takanaga, I. Tamai, S. Inaba, Y. Sai, H. Higashida, H. Yamamoto, and A. Tsuji. cDNA cloning and functional characterization of rat intestinal monocarboxylate transporter. Biochem. Biophys. Res. Commun. 217:370–377 (1995).

    Google Scholar 

  66. I. Osiecka, P. A. Porter, R. T. Borchardt, J. A. Fix, and C. R. Gardner. In vitro drug absorption models. I. Brush border membrane vesicles, isolated mucosal cells and everted intestinal rings: Characterization and salicylate accumulation. Pharm. Res. 2:284–293 (1985).

    Google Scholar 

  67. H. Takanaga, I. Tamai, and A. Tsuji. pH-Dependent and carrier-mediated transport of salicylic acid across Caco-2 cells. J. Pharm. Pharmacol. 46:567–570 (1994).

    Google Scholar 

  68. A. Tsuji, H. Takanaga, I. Tamai, and T. Terasaki. Transcellular transport of benzoic acid across Caco-2 cells by a pH-dependent and carrier-mediated transport mechanism, Pharm. Res. 11:30–37 (1994).

    Google Scholar 

  69. I. Tamai, H. Takanaga, H. Maeda, T. Ogihara, M. Yoneda, and A. Tsuji. Proton-cotransport of pravastatin across intestinal brush-border membrane. Pharm. Res. 12:1727–1732 (1995).

    Google Scholar 

  70. W. Berner, R. Kinne, and H. Murer. Phosphate transport into brush-border membrane vesicles isolated from rat small intestine. Biochem. J. 160:467–474 (1976).

    Google Scholar 

  71. S. M. Borowitz and F. K. Ghishan. Phosphate transport in human jejunal brush-border membrane vesicles. Gastroenterology 96:4–10 (1989).

    Google Scholar 

  72. A. Tsuji and I. Tamai. Na+ and pH dependent transport of foscarnet via the phosphate carrier system across intestinal brush-border membrane. Biochem. Pharmacol. 38:1019–1022 (1989).

    Google Scholar 

  73. P. W. Swaan and J. J. Tukker. Carrier-mediated transport mechanism of foscarnet (trisodium phosphonoformate hexahydrate) in rat intestinal tissue. J. Pharmacol. Exp. Ther. 272:242–247 (1994).

    Google Scholar 

  74. T. Ishizawa, A. Tsuji, I. Tamai, T. Terasaki, K. Hosoi, and S. Fukatsu. Sodium and pH dependent carrier-mediated transport of antibiotic, fosfomycin, in the rat intestinal brush-border membrane. J. Pharmacobio-Dyn. 13:292–300 (1990).

    Google Scholar 

  75. T. Ishizawa, S. Sadahiro, K. Hosoi, I. Tamai, T. Terasaki, and A. Tsuji. Mechanisms of intestinal absorption of the antibiotic, fosfomycin, in brush-border membrane vesicles in rabbits and humans. J. Pharmacobio-Dyn. 15:481–489 (1992).

    Google Scholar 

  76. T. Ishizawa, M. Hayashi, and S. Awazu. Effect of carrier-mediated transport system on intestinal fosfomysin absorption in situ and in vivo. J. Pharmacobio-Dyn. 14:82–86 (1991).

    Google Scholar 

  77. F. A. Wilson. Intestinal transport of bile acids. Am. J. Physiol. 241:G83–G92 (1981).

    Google Scholar 

  78. M. H. Wong, P. Oelkers, A. L. Craddock, and P. A. Dawson. Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter. J. Biol. Chem. 269:1340–1347 (1994).

    Google Scholar 

  79. W. Kramer, G. Wess, G. Neckermann, G. Schubert, J. Fink, F. Girbig, U. Gutjahr, S. Kowalewski, K.-H. Baringhaus, G. Boger, A. Enhsen, E. Falk, M. Friedrich, H. Glombik, A. Hoffmann, C. Pittius, and M. Urmann, Intestinal absorption of peptides by coupling to bile acids. J. Biol. Chem. 269:10621–10627 (1994).

    Google Scholar 

  80. M. T. Simanjuntak, I. Tamai, T. Terasaki, and A. Tsuji. Carrier-mediated uptake of nicotinic acid by rat intestinal brush-border membrane vesicles and relation to monocarboxylic acid transport. J. Pharmacobio-Dyn. 13:301–309 (1990).

    Google Scholar 

  81. H. Takanaga, H. Maeda, I. Tamai, H. Higashida, and A. Tsuji. Nicotinic acid transport mediated by pH-dependent anion antiporter and proton cotransporter in rabbit intestinal brush-border membrane. J. Pharm. Pharmacol. in press.

  82. R. C. Rose. Intestinal transport of water-soluble vitamins. In S. G. Schultz (ed.), Handbook of Physiology, American Physiological Society, Bethesda, MD, pp. 421–435 (1991).

    Google Scholar 

  83. H. M. Said, F. K. Ghishan, and R. Redha. Folate transport by intestinal brush-border membrane vesicles. Am. J. Physiol. 252:G229–G236 (1987).

    Google Scholar 

  84. H. M. Said and R. Redha. A carrier-mediated transport for folate in basolateral membrane vesicles of rat small intestine. Biochem. J. 247:141–146 (1987).

    Google Scholar 

  85. J. Zimmerman. Methotrexate transport in the human intestine. Biochem. Pharmacol. 43:2377–2383 (1992).

    Google Scholar 

  86. H. Matsue, K. G. Rothberg, A. Takashima, B. A. Kamen, R. G. W. Anderson, and S. W. Lacey. Folate receptor allows cells to grow in low concentrations of 5-methyltetrahydrofolate. Proc. Natl. Acad. Sci. USA 89:6006–6009 (1992).

    Google Scholar 

  87. H. Saitoh, M. Kobayashi, M. Sugawara, K. Iseki, and K. Miyazaki. Carrier-mediated transport system for choline and its related quaternary ammonium compounds on rat intestinal brush-border membrane. Biochim. Biophys. Acta 1112:153–160 (1992).

    Google Scholar 

  88. G. R. Herzberg and J. Lerner. Intestinal absorption of choline in the chick. Biochim. Biophys. Acta 307:234–242 (1972).

    Google Scholar 

  89. Z. C. Gatmaitan and I. M. Arias. Structure and function of P-glycoprotein in normal liver and small intestine. Adv. Pharmacol. 24:77–97 (1993).

    Google Scholar 

  90. D. Leveque and F. Jehl. P-glycoprotein and pharmacokinetics. Anticancer Res. 15:331–336 (1995).

    Google Scholar 

  91. A. H. Schinkel, J. J. M. Smit, O. van Tellingen, J. H. Beijnen, E. Wagnenaar, L. van Deemter, C. A. A. M. Mol, M. A. van der Valk, E. C. Robanus-Maandag, H. P. J. te Riele, A. J. M. Berns, and P. Borst. Distruction of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491–502 (1994).

    Article  CAS  PubMed  Google Scholar 

  92. A. Tsuji, T. Terasaki, Y. Takabatake, Y. Tenda, I. Tamai, T. Yamashita, S. Moritani, T. Tsuruo, and J. Yamashita. P-glycoprotein as drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci. 51:1427–1437 (1992).

    Google Scholar 

  93. A. Tsuji, I. Tamai, A. Sakata, Y. Tenda, and T. Terasaki. Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, p-glycoprotein. Biochem. Pharmacol. 46:1096–1099 (1993).

    Google Scholar 

  94. A. Sakata, I. Tamai, K. Kawazu, Y. Deguchi, T. Ohnishi, A. Saheki, and A. Tsuji. In vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood-brain barrie. Biochem. Pharmacol. 48:1989–1992 (1994).

    Google Scholar 

  95. T. Ohnishi, I. Tamai, K. Sakanaka, A. Sakata, T. Yamashima, J. Yamashita, and A. Tsuji. In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier. Biochem. Pharmacol. 49:1541–1544 (1995).

    Google Scholar 

  96. J. Hunter, B. H. Hirst, and N. L. Simmons. Epithelial secretion of vinblastine by human intestinal adenocarcinoma cell (HCT-8 and T84) layers expressing P-glycoprotein. Br. J. Cancer 64:437–444 (1991).

    Google Scholar 

  97. M. B. Meyers, K. W. Scitto, and F. M. Sirotnak. P-Glycoprotein content and mediation of vincristine efflux: correlation with the level of differentiation in luminal epithelium of mouse small intestine. Cancer Commun. 3:159–165 (1991).

    Google Scholar 

  98. J. Hunter, B. H. Hirst, and N. L. Simmons. Drug absoprtion limited by P-glycoprotein-mediated secretory drug transport in human intestinal epithelial Caco-2 cell layers. Pharm. Res. 10:743–749 (1993).

    Google Scholar 

  99. B.-L. Leu and J.-D. Huang. Inhibition of P-glycoprotein and effects on etoposide absorption. Cancer Chemother. Pharmacol. 35:432–436 (1995).

    Google Scholar 

  100. V. Phung-Ba, A. Warnery, D. Schermann, and P. Wils. Interaction of pristinamycin IA with P-glycoprotein in human intestinal epithelial cells. Eur. J. Pharmacol. 288:187–192 (1995).

    Google Scholar 

  101. P. A. Augustijns, T. Timothy, P. Badshaw, L.-S. L. Gan, R. W. Hendren, and D. R. Thakker. Evidence for a polarized efflux system in Caco-2 cells capable of modulating cyclosporn A transport. Biochem. Biophys. Res. Commun. 197:360–365 (1993).

    Google Scholar 

  102. P. S. Burton, R. A. Conradi, A. R. Hilgers, and N. H. Ho. Evidence for a polarized efflux system for peptides in the apical membrane of Caco-2 cells. Biochem. Biophys. Res. Commun. 190:760–766 (1993).

    Google Scholar 

  103. J. Karlsson, S.-M. Kuo, J. Ziemniak, and P. Artursson. Transport of celiprolol across human epithelial (Caco-2) cells: mediation of secretion by multiple transporters including P-glycoprotein. Br. J. Pharmacol. 110:1009–1016 (1993).

    Google Scholar 

  104. H. Saitoh and B. J. Aungst. Possible involvement of multiple P-glycoprotein-mediated efflux system in the transport of verapamil and other organic cations across rat intestine. Pharm. Res. 12:1304–1310 (1995).

    Google Scholar 

  105. S. Hsing, Z. C. Gatmaitan, and I. M. Arias. The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa. Gastroenterology 102:879–885 (1992).

    Google Scholar 

  106. M. Naito, H. Tsuge, C. Kuroko, T. Koyama, A. Tomida, T. Tatsuya, Y. Heike, and T. Tsuruo. Enhancement of cellular accumulation of cyclosporine by anti-P-glycoprotein monoclonal antibody MRK-16 and synergistic modulation of multidrug resistance. J. Natl. Cancer Inst. 85:311–316 (1993).

    Google Scholar 

  107. I. Komiya, J. Y. Park, A. Kamani, N. F. H. Fo., and W. I. Higuchi. Quantitative mechanistic studies in simultaneous fluid flow and intestinal absorption using steroids as model solutes. Int. J. Pharm. 4:249–262 (1980).

    Google Scholar 

  108. Y. C. Martin. A practitioner's perspective of the role of quantitative structure-activity analysis in medicinal chemistry. J. Med. Chem. 24:229–237 (1981).

    Google Scholar 

  109. D. C. Taylor, R. Pownall, and W. Burke. The absorption of β-adrenoreceptor antagonists in rat in-situ small intestine; The effect of lipophilicity. J. Pharm. Pharmacol. 37:280–283 (1985).

    Google Scholar 

  110. S. J. Cirrier, K. Ueda, M. C. Willingham, I. Pastan, and M. Gottesman. Deletion and insertion mutant of the multidrug transporter. J. Biol. Chem. 264:14376–14381 (1989).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsuji, A., Tamai, I. Carrier-Mediated Intestinal Transport of Drugs. Pharm Res 13, 963–977 (1996). https://doi.org/10.1023/A:1016086003070

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016086003070

Navigation