Transporters, Trojan horses and therapeutics: Suitability of bile acid and peptide transporters for drug delivery

Biological Chemistry

Volumn 392, Issue 1-2, 2011, Pages 77-94

  Kramer, Werner ^a  

^a SANOFI AVENTIS DEUTSCHLAND GMBH   (Germany)

Author keywords

bile acid prodrugs; bile acid transporters; drug conjugates; drug delivery; peptide transporters; transporter proteins

Indexed keywords

BILE ACID; BIOTIN; CARRIER PROTEIN; GLUCOSE TRANSPORTER 1; ION CHANNEL; LIGAND; PEPTIDE; PEPTIDE TRANSPORTER 1; PEPTIDE TRANSPORTER 2; PRODRUG; VALACICLOVIR;

APICAL MEMBRANE; ARTICLE; BINDING AFFINITY; BRUSH BORDER; CHEMICAL MODIFICATION; DRUG ABSORPTION; DRUG DELIVERY SYSTEM; DRUG DEVELOPMENT; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG TRANSPORT; GENE OVEREXPRESSION; HOMEOSTASIS; MEMBRANE TRANSPORT; NONHUMAN; PHARMACOPHORE; PRIORITY JOURNAL; STRUCTURE ACTIVITY RELATION;

BILE ACIDS AND SALTS; DRUG DELIVERY SYSTEMS; MEMBRANE TRANSPORT PROTEINS; MOLECULAR STRUCTURE;

EQUIDAE;

EID: 78651364263     PISSN: 14316730     EISSN: 14374315     Source Type: Journal    
DOI: 10.1515/BC.2011.017     Document Type: Article

References (155)

1. Agarwal, S., Boddu, S.H.S., Jain, R., Samanta, S., Pal, D., and Mitra, A.K. (2008). Peptide prodrugs: improved oral absorption oflopinavir, a HIV protease inhibitor. Int. J. Pharm. 359, 7-14.
2. Anelli, P.L., Lattuda, L., Lorusso, V, Lux, G., Morisetti, A., Moro-sini, R., Serleti, M., and Uggeri, F. (2004). Conjugates ofgado-lininium complexes to bile acids as hepatocyte-directed contrast agents for magnetic resonance imaging. J. Med. Chem. 47, 3629-3641.
3. Balakrishnan, A. and Polli, J.E. (2006). Apical sodium dependent bile acid transporter (ASBT, SLC10A2): a potential prodrug tar-get. Mol. Pharm. 3, 223-230.
4. Balimane, P.V., Tamai, I., Guo, A., Nakanishi, T., Kitada, H., Lei-bach, F.H., Tsiji, A., and Sinko, PJ. (1998). Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem. Biophys. Res. Commun. 250, 246-251.
5. +/bile acid cotransporter. J. Lipid Res. 40, 2158-2168.
6. Berczeller, A. (1948). Bile acid derivatives of arylsulfonamides. United States Patent 2,441,129.
7. Betebenner, D.A., Carney, P.L., Zimmer, A.M., Kazikiewicz, J.M., Brücher, E., Sherry, A.D., and Johnson, D.K. (1991). Hepato-biliary delivery ofpolyaminopolycarboxylate chelates: synthesis and characterization of a cholic acid conjugate of EDTA and biodistribution and imaging studies with its Indium-111 cholate. Bioconjug. Chem. 2, 117-123.
8. Bhat, L., Jandeleit, B., Dias, T.M., Moors, T.L., and Gallop, M.A. (2005). Synthesis and biological evaluation of novel steroidal pyrazoles as substrates for bile acid transporters. Bioorg. Med. Chem. Lett. 15, 85-87.
9. +/peptide cotransporter PEPT1. J. Med. Chem. 48, 4410-4419.
10. +/peptide symporter PEPT2: structure-affinity relationships. Amino Acids 31, 137-156.
11. Boll, M., Markorich, D., Weber, W.M., Korte, H., Daniel, H., and Murer, H. (1994). Expression cloning of a cDNA from rabbit small intestine related to proton-coupled transport of peptides, β-lactam antibiotics and ACE-inhibitors. Pflügers Arch. 429, 146-149.
12. Bossuyt, X., Müller, M., and Meier, PJ. (1996). Multispecific amphipathic substrate transporter by an organic anion tranporter of human liver. J. Hepatol. 25, 733-738.
13. Brandsch, M. (2009). Transport of drugs by proton-coupled peptide transporters: pearls and pitfalls. Expert Opin. Drug Metab. Toxi-col. 5, 887-905.
14. Brandsch, M., Knütter, J., and Bosse-Denecke, E. (2008). Pharma-ceutical and pharmacological importance of peptide transporters. J. Pharm. Pharmacol. 60, 543-585.
15. Burckhardt, G., Kramer, W., Kurz, G., and Ullrich, KJ. (1987). Pho-toaffinity labelling studies of the rat renal sodium bile salt cotransport system. Biochem. Biophys. Res. Commun. 143, 1018-1023.
16. Campazzi, E., Cattabriga, M., Marvelli, L., Marchi, A., Rossi, R., Pieragnoli, M.R., and Fogagnolo, M. (1999). Organometallic radiopharmaceuticals: rhenium (I) carbonyl complexes ofnatural bile acids and derivatives. Inorg. Chim. Acta 286, 46-54.
17. Cha, S.H., Sekine, T., Fukushima, J.I., Kanai, Y., Kobayashi, Y., Goya, T., and Endou, H. (2001). Identification and characterization of human organic transporter 3 expressing predominantly in the kidney. Mol. Pharmacol. 59, 1277-1286.
18. Chen, L., Pawlikowski, B., Schlessinger, A., Move, S.S., Stryke, D., Johns, SJ., Portman, M.A., Chen, E., Ferrin, T.E., Sali, A., et al. (2010). Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenet. Genomics 20, 687-699.
19. Criado, JJ., Herrera, M.C., Palomero, M.F., Medarde, M., Rodri-guez, E., and Marin, JJ.G. (1997). Synthesis and characteriza-tion of a new bile acid and platinum (II) complex with cytostatic activity. J. Lipid Res. 38, 1022-1032.
20. Cui, Y., König, J., and Keppler, D. (2001). Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pumps ABCC2. Mol. Pharma-col. 60, 934-943.
21. Cundy, K.C., Branch, R., Chernov-Rogan, T., Dias, T., Estrada, T., Hold, K., Koller, K., Liu, X., Mann, A., Panuwat, M., et al. (2004). XP13512 [(±)-1-([(α-Isobutanoloxyethoxy)carbonyl]-aminomethyl) -1-cyclohexane acetic acid], a novel gabapentin prodrug: I. design, synthesis, enzymatic conversion to gabapen-tin, and transport by intestinal solute transporters. J. Pharm. Exp. Ther. 311, 315-323.
22. Cundy, K.C., Sastry, S., Luo, W., Zou, J., Moors, T.L., and Canafax, D.M. (2008). Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin. J. Clin. Pharmacol. 48, 1378-1388.
23. Dalpiaz, A., Pavan, B., Scaglianti, M., Vitali, F., Bortolotti, F., Bon-di, C., Scatturin, A., and Manfredini, S. (2005). Vitamin C and 6-amino-vitamin C conjugates of diclofenac: synthesis and eval-uation. Int. J. Pharm. 291, 171-181.
24. Dawson, P.A., Hubbert, M., Haywood, J., Craddock, A.L., Zerangue, N., Christian, W.V., and Ballatori, N. (2005). The heteromeric organic solute transporter α-β, Ostα-Ostβ, is an ile-al basolateral bile acid transporter. J. Biol. Chem. 280, 6960-6968.
25. Dawson, P.A., Lan, T., and Rao, A. (2009). Bile acid transporters. J. Lipid Res. 50, 2340-2357.
26. Dobson, P.D. and Kell, D.B. (2008). Carrier-mediated cellular uptake of pharmaceutical drugs: an exception of the rule? Nat Rev. Drug Discov. 7, 205-220.
27. Ekins, S., Johnston, J.S., Bahadduri, P., D'Souza, V.M., Ray, A., Chang, C., and Swaan, P.W. (2005). In vitro and pharmacophore-based discovery of novel hPEPT1 inhibitors. Pharm. Res. 22, 512-517.
28. Eriksson, A.H., Varma, M.V.S., Perkins, E.J., and Zimmerman, C.L. (2010). The intestinal absorption of a prodrug of the mGlu2/3 receptor agonist LY354740 is mediated by PEPT1: in situ rat intestinal perfusion studies. J. Pharm. Sci. 99, 1574-1581.
29. Fei, YJ., Kanai, Y., Nussberger, S., Ganapathy, V, Leibach, F.H., Romero, M.F., Singh, S.K., Boron, W.F., and Hediger, M.A. (1994). Expression cloning of a mammalian proton-coupled oli-gopeptide transporter. Nature 368, 563-566.
30. Fernández, C., Nieto, O., Fontenla, J.A., Rivas, E., de Ceballos, M.L., and Alfonso, F.-M. (2003). Synthesis of glycosyl deriva-tives as dopamine prodrugs: interaction with glucose carrier GLUT-1. Org. Biomol. Chem. 1, 767-771.
31. Foley, D., Bailey, P., Pieri, M., and Meredith, D. (2009a). Targeting ketone drugs towards transport by the intestinal peptide trans-porter, PepT1. Org. Biomol. Chem. 7, 1064-1067.
32. Foley, D., Pieri, M., Pettecrew, R., Price, R., Miles, S., Lam, H.K., Bailey, P., and Meredith, D. (2009b). The in vitro transport of model thiodipeptide prodrugs designed to target the intestinal oligopeptide transporter, PepT1. Org. Biomol. Chem. 7, 3652-3656.
33. Foley, D.W., Rajamanickam, J., Bailey, P.D., and Meredith, D. (2010). Bioavailability through PepT1: the role of computer modelling in intelligent drug design. Curr. Comput. Aided Des. 6, 68-78.
34. Franke, R.M. and Sparreboom, A. (2010). Drug transporters: recent advances and therapeutic applications. Clin. Pharmacol. Ther. 87, 3-7.
35. Ganapathy, M.E., Huang, W., Wang, H., Ganapathy, V, and Leibach, F.H. (1998). Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem. Biophys. Res. Commun. 246, 470-475.
36. Gerloff, T., Stieger, B., Hagenbuch, B., Madon, J., Landmann, L., Roth, J., Hofmann, A.F., and Meier, PJ. (1998). The sister of p-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem. 273, 10046-10050.
37. Giacomini, K.M., Huang, S.-W., Tweedie, DJ., Benet, L.Z., Brou-wer, K.L.R., Chu, X., Dahlin, A., Evers, R., Fischer, V, Hillgren, K.M., et al. (2010). Membrane transporters in drug development. Nat. Rev. Drug Discov. 9, 215-236.
38. Gong, Y.Z., Everett, E.T., Schwartz, D.A., Norris, J.S., and Wilson, FA. (1994). Molecular cloning, tissue distribution, and expres-sion of a 14-kDa bile acid-binding protein from rabbit ileal cytosol. Proc. Natl. Acad. Sci. USA 91, 4741-4745.
39. Grube, M., Köck, K., Oswald, S., Draber, K., Meisner, K., Eckel, L., Böhm, M., Felix, S.B., Vogelsang, S., Jedlitschky, G., 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, 602-620.
40. Gunaseelan, S., Debrah, O., Wan, L., Leibowitz, M.J., Rabson, A.B., Stein, S., and Sinko, P.J. (2004). Synthesis ofpoly(ethylene gly-col)-based saquinavir prodrug conjugates and assessment of release and anti-HIV-1 bioactivity using a novel protease inhi-bition assay Bioconj. Chem. 15, 1322-1333.
41. Gynther, M., Ropponen, J., Laine, K., Legpänen, J., Haapakoski, P., Peura, L., Järvinen, T., and Rautio, J. (2009). Glucose promoiety enables glucose transporter mediated brain uptake by ketoprofen and indomethacin prodrugs in rats. J. Med. Chem. 52, 3348-3353.
42. Hagenbuch, B. and Gui, C. (2008). Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 38, 778-801.
43. +/bile acid cotransporter in Xenopus laevis oocytes. J. Biol. Chem. 265, 5357-5360.
44. Hatano, S., Yoshida, H., Matsunami, M., Ide, Y., Matsuda, K., Yat-sunami, T., Fuwa, T., Khira, K., Kuramoto, T., and Hoshita, T. (1991). Absorption, biliary excretion and metabolism of a new cholelithocyclic agent, ursodeoxycholyl-N-carboxymethyl-gly-cine and its esters in rats. J. Pharmacobiol. Dyn. 14, 561-566.
45. Hemmings, H.C. Jr., Akabas, M.H., Goldstein, P.A., Trudell, J.R., Orser, B.A., and Harrison, N.L. (2005). Emerging molecular mechanisms of general anaesthetic action. Trends Pharmacol. Sci. 26, 503-510.
46. Hilgenbrink, A.R. and Low, P.S. (2005). Folate receptor-mediated drug targeting: from therapeutics to diagnostics. J. Pharm. Sci. 94, 2135-2148.
47. Ho, N.FH. (1987). Utilizing bile acid carrier mechanisms to enhance liver and small intestine absorption. Ann. N.Y. Acad. Sci. 907, 315-329.
48. Ho, R.H., Tirona, R.G., Leake, B.F., Glaeser, H., Lee, W., Lemke, CJ., Wang, J., and Kim, R.B. (2006). Drug and bile acid trans-porter in vosuvastatin hepatic uptake: function expression and pharmacogenetics. Gastroenterology 130, 1793-1806.
49. Huang, S.-M. and Woodcock, J. (2010). Transporters in drug devel-opment: advancing on the critical path. Nat. Rev. Drug Discov. 9, 175-176.
50. +-coupled active transport of bestatin via the dipep-tide transport system in rabbit intestinal brush-border mem-branes. J. Pharmacol. Exp. Ther. 260, 482-486.
51. Kagedahl, M., Swaan, P.W., Redemann, C.T., Tang, M., Craik, C.S., Szoka, F.C. Jr., and Oie, S. (1997). Use of the intestinal bile acid transporter for the uptake of cholic acid conjugates with HIV-1 protease inhibitory activity. Pharm. Res. 14, 176-180.
52. Kannan, A., DeClerq, E., Pannecouque, C., Witrrouw, M., Hartman, T.L., Turpin, J.A., Buckheit, R.W. Jr., and Cushman, M. (2001). Synthesis and anti-HIV activity of a bile acid analog of cosalane. Tetrahedron 57, 9285-9391.
53. Khamdang, S., Takeda, M., Babu, E., Noshiro, R., Onozato, M.L., Tojo, A., Enomoto, A., Huang, X.L., Narikawa, S., Anzai, N., et al. (2003). Interaction of human and rat organic anion trans-porter 2 with various cephaosporin antibiotics. Eur. J. Pharma-col. 465, 1-7.
54. Kim, D.C., Harrison, A.W., Ruwart, MJ., Wilkinson, K.F., Fischer, FJ., Hidalgo, I.J., and Borchardt, R.T. (1993). Evaluation ofbile acid transporter in enhancing intestinal permeability to rennin-inhibitory peptides. J. Drug Target. 1, 347-359.
55. Kimura, N., Masuda, S., Tanihara, Y., Ueo, H., Okuda, M., Katsura, T., and Inui, K. (2005a). Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug. Metab. Pharmacokinet. 20, 379-386.
56. Kimura, N., Okuda, M., and Inui, K. (2005b). Metformin transport by renal basolateral organic cation transporter hOCT2. Pharm. Res. 22, 255-259.
57. Klaassen, C.D. and Aleksunes, L.M. (2010). Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol. Rev. 62, 1-96.
58. Koepsell, H., Lips, K., and Volk, C. (2007). Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm. Res. 24, 1227-1251.
59. Konikoff, F.M. and Gilat, T. (2005). Effects of fatty acid bile acid conjugates (FABACs) on biliary lithogenesis: potential conse-quences for non-surgical treatment of gallstones. Curr. Drug Tar-gets Immune Endocr. Metabol. Disord. 5, 171-175.
60. Kopplow, K., Letschert, K., König, J., and Keppler, D. (2005). Human hepatobiliary transport of organic anions analysed by quadruple-transfected cells. Mol. Pharmacol. 68, 1031-1038.
61. Kramer, W. (1995). Identification of the bile acid binding proteins in human serum by photoaffinity labelling. Biochim. Biophys. Acta 1257, 230-238.
62. Kramer, W. and Wess, G. (1989). European Patent Application EP 0417725A2.
63. Kramer, W. and Wess, G. (1996). Bile acid transport systems as pharmaceutical targets. Eur. J. Clin. Invest. 26, 715-732.
64. Kramer, W. and Glombik, H. (2006). Bile acid reabsorption inhib-itors (BARI): novel hypolipidemic drugs. Curr. Med. Chem. 13, 997-1016.
65. Kramer, W., Buscher, H.-P., Gerok, W., and Kurz, G. (1978). Bile salt binding to serum components. Taurocholate incorporation into high-density lipoprotein revealed by photoaffinity labelling. Eur. J. Biochem. 102, 1-9.
66. Kramer, W., Girbig, F., Gutjahr, U., Kleemann, H.-W., Leipe, J., Urbach, H., and Wagner, A. (1990). Interaction of renin inhibi-tors with the intestinal uptake system for oligopeptides and β-lactam antibiotics. Biochim. Biophys. Acta 1027, 25-30.
67. Kramer, W., Wess, G., Schubert, G., Bickel, M., Girbig, F., Gutjahr, U., Kowalewski, S., Baringhaus, K.-H., Enhsen, A., Glombik, H., et al. (1992). Liver-specific drug targeting by coupling to bile acids. J. Biol. Chem. 267, 18598-18604.
68. Kramer, W., Wess, G., Schubert, G., Bickel, M., Hoffmann, A., Baringhaus, K.-H., Enhsen, A., Glombik, H., Müller, S., Nec-kermann, G., et al. (1993). Bile acids as carriers for drugs. Falk Symp. 68, 161-176.
69. Kramer, W., Wess, G., Neckermann, G., Schubert, G., Fink, J., Gir-big, F., Gutjahr, U., Kowalewski, S., Baringhaus, K.-H., Böger, G., et al. (1994a). Intestinal absorption of peptides by coupling to bile acids. J. Biol. Chem. 269, 10621-10627.
70. Kramer, W., Wess, G., Enhsen, A., Bock, K., Falk, E., Hoffmann, A., Neckermann, G., Gantz, D., Schulz, S., Nickau, L., et al. (1994b). Bile acid derived HMG-CoA reductase inhibitors. Bio-chim. Biophys. Acta 1227, 137-154.
71. Kramer, W., Girbig, F., Gutjahr, U., and Kowalewski, S. (1995). The intestinal oligopeptide transporter: molecular characterization and substrate specificity In: Peptide-Based Drug Design. Con-trolling Transport and Metabolism, M.D. Taylor and G.L. Ami-don, eds. (ACS Professional Reference Book, American Chemical Society, Washington, DC, USA), pp. 149-179.
72. Kramer, W., Wess, G., Enhsen, A., Falk, E., Hoffmann, A., Nec-kermann, G., Schubert, G., and Urmann, M. (1997). Modified bile acids as carriers for peptides and drugs. J. Control. Release 46, 17-30.
73. +/bile acid contransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters. J. Lipid Res. 40, 1604-1617.
74. +/bile acid cotransporting protein from rabbit ileum. J. Biol. Chem. 276, 36020-36027.
75. Kullak-Ublick, G.-A., Glasa, J., Böker, C., Oswald, M., Grützner, U., Hagenbuch, B., Stieger, B., Meier, P.J., Beuers, U., Kramer, W., et al. (1997). Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas. Gastroenterology 113, 1295-1305.
76. Kullak-Ublick, G.A., Ismair, M.G., Stieger, B., Landmann, L., Huber, R., Pizzagalli, F., Fattinger, K., Meier, P.J., and Hagen-buch, B. (2001). Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATP's of human liver. Gastoentrology 120, 525-533.
77. Lack, L. (1979). Properties and biological significance of the ileal bile salt transport system. Environ. Health Perspect. 33, 79-90.
78. Lack, L. and Weiner, I.M. (1966). Intestinal bile salt transport: struc-ture-activity relationships and other properties. Am. J. Physiol. 210, 1142-1152.
79. Lal, R., Sukbantheng, J., Tai, E.H., Upadhyay, S., Yao, F., Warren, M.S., Luo, W., Bu, L., Nguyen, S., Zamora, J., et al. (2009). Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen. J. Pharmacol. Exp. Ther. 330, 911-921.
80. Letschert, K., Komatsu, M., Hummel-Eisenbeiss, J., and Keppler, D. (2005). Vectorial transport of the peptide CCK-8 by double-transtected MDCKII cells stably expressing the organic anion transporter OATP1B3 (OATP8) and the export pump ABCC2. J. Pharmacol. Exp. Ther. 313, 549-556.
81. Li, P., Wang, G.-J., Robertson, T.A., and Roberts, M.S. (2009). Liver transporters in hepatic drug disposition: an update. Curr. Drug Metab. 10, 482-498.
82. Lin, J., Kolar, C., Lawson, T.A., and Gmeiner, W.H. (2001). Tar-geted drug delivery to chemoresistant cells: folic acid derivati-zation of Fd4MP[10] enhances cytotoxicity toward 5-FU-resistant human colorectal tumor cells. J. Org. Chem. 66, 5655-5663.
83. Lipinski, C.A., Lombardo, F., Dominy, B.W., and Feeney, P.J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3-25.
84. Lischka, K., Starke, D., Failing, K., Herling, A., Kramer, W., and Petzinger, E. (2003). Hepatobiliary elimination of bile-acid mod-ified oligodeoxynucleotides in Wistar and TR-rats: evidence for mrp2 as carrier for oligodeoxynucleotides. Biochem. Pharm. 66, 565-577.
85. Liu, Y.-S., Tungpradit, R., Sinchaikul, S., An, F.-M., Lin, D.-Z., Phutrakul, S., and Chen, S.-T. (2008). Targeting the delivery of glycan-based paclitaxel prodrugs to cancer cells via glucose transporters. J. Med. Chem. 51, 7428-7441.
86. Luo, S., Kansara, V.S., Zhu, X., Pal, D., and Mitra, A.K. (2006). Functional characterization of sodium-dependent multivitamin transporter (SMVT) in MDCK-MDR1 cells and its utilization as a target for drug delivery Mol. Pharm. 3, 329-339.
87. Maglova, L.M., Jackson, A.M., Meng, X.-J., Carruth, M.W., Schteingart, C.D., Ton-Nu, H.T., Hofmann, A.F., and Weinman, S.A. (1995). Transport characteristics of three fluorescent con-jugated bile acid analogs in isolated rat hepatocyte and couplets. Hepatology 22, 637-647.
88. McGarry, D.G., Volz, F.A., Regan, J.R., and Chang, M.N. (1993). Compound having hypocholesterolemic properties. United States Patent 52160015.
89. Menear, K.A., Patel, D., Clay, V, Howes, C., and Taylor, P.W (1992). A novel approach to the site specific delivery of poten-tial HMG-CoA reductase inhibitors. Bioorg. Med. Chem. Lett. 2, 285-290.
90. Miller, K.W. (2002). The nature of sites of general anaesthetic action. Br. J. Anaesth. 89, 17-31.
91. Minko, T., Paranjpe, P.V., Qiu, B., Llalloo, A., Won, R., Stein, S., and Sinko, PJ. (2002). Enhancing the anticancer efficacy of camptothecin using biotinylated poly(ethleneglycol) conjugates in sensitive and multidrug resistant human ovarian carcinoma cells. Cancer Chemother. Pharmacol. 50, 143-150.
92. Monte, MJ., Dominguez, S., Palomero, M.F., Marcias, RJ., and Marin, JJ. (1999). Further evidence for the usefulness of bile acids as molecules for shuttling cytostatic drugs toward liver tumors. J. Hepatol. 31, 521-528.
93. Monte, MJ., Marin, J.J.G., Antelo, A., and Vasquez-Tato, J. (2009). Bile acids: chemistry, physiology, and pathophysiology World J. Gastroenterol. 15, 804-816.
94. Nielsen, C.U. and Brodin, B. (2003). Di/tri-peptide transporters as drug delivery targets: regulation oftransport under physiological and patho-physiological conditions. Curr. Drug Targets 4, 373-388.
95. Oelkers, P. and Dawson, P.A. (1995). Cloning and chromosomal localization of the human ileal lipid-binding protein. Biochim. Biophys. Acta 1257, 199-202.
96. +-coupled uphill transport of aminocephalosporins via the dipeptide transport system in rabbit intestinal brush-border membranes. J. Biol. Chem. 261, 14130-14136.
97. Omkvist, D.H., Larsen, S.B., Nielsen, C.U., Steffansen, B., Olsen, L., Jorgensen, F.S., and Brodin, B. (2010). A quantitative struc-ture-activity relationship for translocation of tripeptides via the human proton-coupled peptide transporter, hPEPT1 (SLC15A1). AAPS J. 12, 385-396.
98. Overington, J.P., Al-Lazikani, B., and Hopkins, A.L. (2006). How many drug targets are there? Nat. Rev. Drug Discov. 5, 993-996.
99. Paschke, R., Kalbitz, J., and Paetz, C. (2000). Novel spacer linked bile acid-cisplatin compounds as a model for specific drug deliv-ery, synthesis, and characterization. Inorg. Chim. Acta 304, 241-249.
100. Qian, S., Wu, J.-B., Wu, X.-C., Li, J., and Wu, Y. (2009). Synthesis and characterization of new liver targeting 5-fluorouracil-cholic acid conjugates. Arch. Pharm. Chem. Life Sci. 342, 513-520.
101. Ramanathan, S., Pooyan, S., Stein, S., Prasad, P.D., Wang, J., Lei-bowitz, M., Ganapathy, V., and Sinko, PJ. (2001). Targeting the sodium-dependent multivitamin transporter (SMVT) for improv-ing the oral absorption properties of a retro-inverso Tat nona-peptide. Pharm. Res. 18, 950-956.
102. Rius, M., Keller, D., Brom, M., Hummel-Eisenbeis, J., Lyko, F., and Keppler, D. (2010). Vectorial transport of nucleoside analogs from the apical to the basolateral membrane in double-trans-fected cells expressing the human concentrative nucleoside transporter hCNT3 and the export pump ABCC4. Drug Metab. Dispos. 38, 1054-1063.
103. Rubio-Aliaga, J. and Daniel, H. (2002). Mammalian peptide trans-porters as targets for drug delivery Trends Pharmacol. Sci. 23, 434-440.
104. Rubio-Aliaga, J. and Daniel, H. (2008). Peptide transporters and their roles in physiological processes and drug disposition. Xenobiotica 38, 1022-1042.
105. Sai, Y. (2005). Biochemical and molecular pharmacological aspects of transporters as determinants of drug disposition. Drug Metab. Pharmacokinet. 20, 91-99.
106. Said, H.M., Mee, L., Sekar, V.T., Ashokkumar, B., and Pandeol, S.J. (2010). Mechanism and regulation offolate uptake by pancreatic acinar cells: effect of chronic alcohol consumption. Am. J. Phy-siol. Gastrointest. Liver Physiol. 298, G985-G993.
107. Saito, H., Terada, T., Okuda, M., Sasaki, S., and Inui, K. (1996). Molecular cloning and tissue distribution of rat peptide trans-porter PEPT2. Biochim. Biophys. Acta 1280, 173-177.
108. Santos, C., Morais, J., Gouveia, L., de Clerq, E., Pannecouque, C., Nielsen, C.U., Steffansen, B., Moreira, R., and Gomes, P. (2008). Dipeptide derivatives of ATZ: synthesis, chemical stability, acti-vation in human plasma, hPEPT1 affinity and antiviral activity. Chem Med Chem 3, 970-978.
109. Sasaki, M., Suzuki, H., Ito, K., Abe, T., and Sugiyama, Y. (2002). Transcellular transport of organic anions across the double-trans-fected Madin-Darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and multidrug resistance-associated protein 2 (MRP2/ABCC2). J. Biol. Chem. 277, 6497-6503.
110. Sasaki, M., Suzuki, H., Aoki, J., Ito, K., Meier, P.J., and Sugiyama, Y. (2004). Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a doube-transfected Madine-Darby canine kidney II monolayer express-ing both rat organic anion transporting polypeptide 4 and multidrug resistance-associated protein 2. Mol. Pharmacol. 66, 450-459.
111. Schinkel, A.H., Wagenaar, E., van Deemter, L., Mol, C., and Borst, P. (1995). Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethason, digoxin, and cyclosporine A. J. Clin. Invest. 96, 1698-1705.
112. Schneider, S., Schramm, U., Schreyer, A., Buscher, H.-P., Gerok, W., and Kurz, G. (1991). Fluorescent derivatives ofbile salts I. Synthesis and properties of NBD-amino derivatives ofbile salts. J. Lipid Res. 32, 1755-1767.
113. Schramm, U., Dietrich, A., Schneider, S., Buscher, H.-P., Gerok, W., and Kurz, G. (1991). Fluorescent derivatives of bile salts. II. Suitability of NBD-amino derivatives ofbile salts for the study of biological transport. J. Lipid Res. 32, 1769-1779.
114. +-bile salt cotransporter in Xenopus laevis oocytes and in CHO cells. Am. J. Physiol. 274, G370-G375.
115. Schteingart, C.D., Eming, S., Ton-Nu, H.-T., Crombie, D.L., and Hofmann, A.F. (1993). Synthesis, structure and transport prop-erties of fluorescent derivatives of conjugated bile acids. In: Bile Acid and Hepatobiliary System. From Basic Science to Clinical Practice, G. Paumgartner, A. Stiehl and W. Gerok, eds. (Dor-drecht, The Netherlands: Kluwer Academic Publishers), pp. 177-183.
116. Shu, Y., Sheardown, S.A., Brown, C., Owen, R.P., Zhang, S., Castro, R.A., Ianculescu, A.G., Yue, L., Lo, J.C., Burchard, E.G., et al. (2007). Effect of genetic variation in the organic cation trans-porter 1 (OCT1) on metformin action. J. Clin. Invest. 117, 1422-1431.
117. Sievänen, E. (2007). Exploitation of bile acid transport systems in prodrug design. Molecules 12, 1859-1889.
118. Smith, AJ., van Helvoort, A., van Meer, G., Szabó, K., Welker, E., Szakács, G., Váradi, A., Sarkadi, B., and Borst, P. (2000). MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J. Biol. Chem. 275, 23520-23539.
119. Song, J.S., Shin, HJ., Shim, E.J., Jung, J.S., Kim, W.Y., Shou, J.H., and Shin, J.G. (2008). Genetic variations of the organic cation transporter 2 influence the disposition of metformin. Clin. Phar-macol. Ther. 84, 559-562.
120. Starke, D., Lischka, K., Pagels, P., Uhlmann, E., Kramer, W., Wess, G., and Petzinger, E. (2001). Bile acid-oligodeoxynucleotide conjugates: synthesis and liver excretion in rats. Bioorg. Med. Chem. Lett. 11, 945-949.
121. Steffansen, B., Nielsen, C.U., and Frokjaer, S. (2005). Delivery aspects of small peptides and substrates for peptide transporters. Eur. J. Pharm. Biopharm. 60, 241-245.
122. Stengelin, S., Apel, S., Becker, W., Maier, M., Rosenberger, J., Bewersdorf, U., Girbig, F., Weyland, C., Wess, G., and Kramer, W. (1996). The rabbit ileal lipid-binding protein. Gene cloning and functional expression of the recombinant protein. Eur. J. Biochem. 239, 887-896.
123. 3 by liver targeting with cholic acid. Biochem. Pharmacol. 43, 1969-1974.
124. St.-Pierre, M.V., Kullak-Ublick, G.A., Hagenbuch, B., and Meier, PJ. (2001). Transport of bile acids in hepatic and non-hepatic tissues. J. Exp. Biol. 204, 1673-1686.
125. Sugawara, M., Huang, W., Fei, YJ., Leibach, F.H., Ganapathy, V, and Ganapathy, M.E. (2000). Transport of Valganciclovir, a gan-ciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J. Pharm. Sci. 89, 781-789.
126. Swaan, P.W., Hillgren, K.M., Szoka, F.C Jr., and Oie, S. (1997). Enhanced transepithelial transport of peptides by conjugation to cholic acid. Bioconj. Chem. 8, 520-525.
127. Takahashi, M., Konishi, T., Maeda, Y., Fukuzawa, M., Nishida, T., Ohya, T., Katayama, K., Kakehi, N., Sakakura, H., Takagi, A., et al. (1998). Basic studies on N"-ursodeoxycholyldiethylene-triamine-N, N, N'-triacetic acid for the dissolution of calcified gallstones. Biol. Pharm. Bull. 21, 551-557.
128. Tamai, I., Nakanishi, T., Nakahara, H., Sai, Y., Ganapathy, V, Lei-bach, F.H., and Tsuji, A. (1998). Improvement of L-dopaabsorption by dipeptidyl-derivation, utilizing peptide transporter PepT1. J. Pharm. Sci. 87, 1542-1546.
129. Tamai, I., Nezu, J., Uchino, H., Say, Y., Oku, A., Shimane, M., and Tsuji, A. (2000). Molecular identification and characterization of novel members of the organic anion transporter (OATP) family. Biochem. Biophys. Res. Commun. 273, 251-260
130. The SEARCH Collaborative Group (2008). SLC01B1 variants and statin-induced myopathy-a genomewide study. N. Engl. J. Med. 359, 789-799.
131. Tolle-Sander, S., Lentz, K.A., Maeda, D.Y., Coop, A., and Polli, J.E. (2004). Increased acyclovir oral bioavailability via a bile acid conjugate. Mol. Pharm. 1, 40-48.
132. Tsume, Y., Vig, B.S., Sun, J., Landowski, C.P., Hilfinger, J.M., Ramachandran, C., and Amidon, G.L. (2008). Enhanced absorp-tion and growth inhibition with amino acid monoester prodrugs of Floxuridine by targeting hPEPT1 transporters. Molecules 13, 1441-1454.
133. Urquhart, B.L., Gregor, J.C., Chande, N., Knauer, M.J., Tirona, R.G., and Kim, R.B. (2010). The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G248-G254.
134. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) (2010). US FDA website [online], http://www.fda.gov/Drugs/GuidanceComplicanceRegulatoryInformation/Guidances/ ucm064982.htm.
135. US Food and Drug Administration (2009). US FDA website [online], http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ DrugInteractionsLabeling/ucm080499. htm.
136. +-D-glucose cotransporter SAAT1. Proc. Natl. Acad. Sci. USA 95, 2914-2919.
137. von Geldern, T., Tu, N., Kym, P.R., Link, J.T., Jae, H.-S., Lai, C., Apelqvist, T., Rhonnstad, P., Hagberg, L., Koehler, K., et al. (2004). Liver-selective glucocorticoid antagonists: a novel treat-ment for type 2 diabetes. J. Med. Chem. 47, 4213-4230.
138. Walker, J.R. and Altman, E. (2005). Biotinylation facilitates the uptake of large peptides by Escherichia coli and other Gram-negative bacteria. Appl. Environ. Microbiol. 71, 1850-1855.
139. Walter, E., Kissel, T., Reers, M., Dickneite, G., Hoffmann, D., and Stüber, W. (1995). Transepithelial transport properties of pepti-domimetic thrombin inhibitors in monolayers of a human intes-tinal cell line (CaCo2) and their correlation to in vivo data. Pharm. Res. 12, 360-365.
140. Wanchana, S., Yamashita, F., Hara, H., Fujiwara, S.-J., Akamatsu, M., and Hashida, M. (2004). Two-and three-dimensional OSAR of carrier-mediated transport of β-lactam antibiotics in CaCo2 cells. J. Pharm. Sci. 93, 3057-3065.
141. Wang, D.-S., Jonker, J.W., Kato, Y., Kusuhara, H., Schinkel, A.M., and Sugiyama, Y (2002). Involvement of organic cation tran-porter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Exp. Ther. 302, 510-515.
142. Wang, L., Cherican, C., Desmoulin, S.K., Polin, L., Deng, Y., Wu, J., Hou, Z., White, K., Kushner, J., Matherly, L.H., et al. (2010). Synthesis and antitumor activity of a novel series of 6-substi-tuted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors and purine biosynthesis with selectivity for high affinity folate trans-porters and the proton-complex folate transporter over the reduced folate carrier for cellular entry. J. Med. Chem. 53, 1306-1318.
143. Weiner, J.M., Glasser, J.E., and Lack, L. (1964). Renal excretion of bile acids: taurocholic, glycholic and cholic acids. Am. J. Phy-siol. 207, 964-970.
144. Wess, G., Kramer, W., Schubert, G., Enhsen, A., Baringhaus, K.-H., Glombik, H., Müllner, S., Bock, K., Kleine, H., John, M., et al. (1993). Synthesis of bile acid-drug conjugates: potential drug-shuttles for liver specific targeting. Tetrahedron Lett. 34, 819-822.
145. Wess, G., Kramer, W., Enhsen, A., Glombik, H., Baringhaus, K.-H., Böger, G., Urmann, M., Bock, K., Kleine, H., Neckermann, G., et al. (1994a). Specific inhibitors of ileal bile acid transport. J. Med. Chem. 37, 873-875.
146. Wess, G., Kramer, W., Han, X.B., Bock, K., Enhsen, A., Glombik, H., Baringhaus, K.-H., Böger, G., Urmann, M., Hoffmann, A., et al. (1994b). Synthesis and biological activity of bile acid-derived HMG-CoA reductase inhibitors. The role of 21-methyl in recognition of HMG-CoA reductase and the ileal bile acid transport system. J. Med. Chem. 37, 3240-3246.
147. Wilson, F.A., Burckhardt, G., Murer, H., Rumrich, G., and Ullrich, K.J. (1981). Sodium-coupled taurocholate transport in the prox-imal convolution of the rat kidney in vivo and in vitro. J. Clin. Invest. 67, 1141-1150.
148. Wong, M.H., Oelkers, P., Craddock, A.L., and Dawson, P.A. (1994). Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter. J. Biol. Chem. 269, 1340-1347.
149. Woo, V.C. (2009). Dapagliflozin: where does it fit in the treatment of type 2 diabetes? Exp. Opin. Pharmacother. 10, 2527-2535.
150. Wu, D., Ji, S., Wu, Y., Ju, Y., and Zhao, Y. (2007). Design, syn-thesis, and antitumor activity of bile acid-polyamine-nucleoside conjugates. Bioorg. Med. Chem. Lett. 17, 2983-2986.
151. Zair, Z.M., Eloranta, JJ., Stieger, B., and Kullak-Ublick, GA. (2008). Pharmacogenetics of OATP (SLC21/SLC0), OAT and OCT (SLC22) and PEPT (SLC15) transporters in the intestine, liver and kidney. Pharmacogenomics 9, 597-624.
152. Zhang, L., Strong, J.M., Qui, W., Lesko, LJ., and Huang, S.M. (2006). Scientific perspectives on drug transporters and their role in drug interaction. Mol. Pharm. 3, 62-69.
153. Zhang, L., Zhang, Y.D., Strong, J.M., Reynolds, K.S., and Huang, S.M. (2008). A regulatory viewpoint on transporter-based drug interactions. Xenobiotica 38, 709-724.
154. Zhao, R. and Goldman, J.D. (2007). The molecular identity and characterization of a proton-coupled folate transporter-PCFT; biological verifications and impact on the activity of peme-trexed. Cancer Metastasis Rev. 26, 129-139.
155. Zheng, X. and Polli, J.E. (2010). Synthesis and in vitro evaluation of potential sustained release prodrugs via targeting ASBT. Int. J. Pharm. 396, 111-118.