Transporter-mediated drug delivery: recent progress and experimental approaches.

A comprehensive list of drug transporters has recently become available as a result of extensive genome analysis, as well as membrane physiology and molecular biology studies. This review covers recent progress in identification and characterization of drug transporters, illustrative cases of successful drug delivery to, or exclusion from, target organs via transporters, and novel experimental approaches to therapeutics using heterologously transduced transporters in tissues. We aim to provide clues that could lead to efficient strategies for the use of transporters to deliver drugs and/or to optimize lead compounds.

[1]  F. Döring,et al.  Delta-aminolevulinic acid transport by intestinal and renal peptide transporters and its physiological and clinical implications. , 1998, The Journal of clinical investigation.

[2]  Kelly H. Jordan,et al.  P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine. , 2003, Journal of pharmaceutical sciences.

[3]  V. Sasseville,et al.  A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2) , 1999, The Journal of Biological Chemistry.

[4]  S. Miyazaki,et al.  In Vivo Activity of HSR-903, a New Fluoroquinolone, against Respiratory Pathogens , 1998, Antimicrobial Agents and Chemotherapy.

[5]  J. Nezu,et al.  Involvement of Human Organic Anion Transporting Polypeptide OATP-B (SLC21A9) in pH-Dependent Transport across Intestinal Apical Membrane , 2003, Journal of Pharmacology and Experimental Therapeutics.

[6]  Y. Sugiyama,et al.  Biliary excretion of pravastatin in rats: contribution of the excretion pathway mediated by canalicular multispecific organic anion transporter. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[7]  P. Meier,et al.  The superfamily of organic anion transporting polypeptides. , 2003, Biochimica et biophysica acta.

[8]  M. Romero,et al.  Expression cloning of a mammalian proton-coupled oligopeptide transporter , 1994, Nature.

[9]  H. Takanaga,et al.  Proton-Cotransport of Pravastatin Across Intestinal Brush-Border Membrane , 1995, Pharmaceutical Research.

[10]  P. Dawson,et al.  Fruit juices inhibit organic anion transporting polypeptide–mediated drug uptake to decrease the oral availability of fexofenadine , 2002, Clinical pharmacology and therapeutics.

[11]  S. Shirazi-Beechey,et al.  Glycyl-L-proline transport in rabbit enterocyte basolateral-membrane vesicles. , 1990, The Biochemical journal.

[12]  U. Christians,et al.  Grapefruit Juice Activates P-Glycoprotein-Mediated Drug Transport , 1999, Pharmaceutical Research.

[13]  T. Karasawa,et al.  [Pharmacological study of ebastine, a novel histamine H1-receptor antagonist]. , 1994, Nihon yakurigaku zasshi. Folia pharmacologica Japonica.

[14]  J. Nezu,et al.  Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. , 2000, Biochemical and biophysical research communications.

[15]  A. Tsuji Transporter-mediated Drug Interactions. , 2002, Drug metabolism and pharmacokinetics.

[16]  R. Schlapbach,et al.  Differential activity of bcl-2 and ICE enzyme family protease inhibitors on Fas and puromycin-induced apoptosis of glioma cells. , 1997, Biochimica et biophysica acta.

[17]  H. Saito,et al.  Interaction of β-Lactam Antibiotics with Histidine Residue of Rat H+/Peptide Cotransporters, PEPT1 and PEPT2* , 1998, The Journal of Biological Chemistry.

[18]  H. Daniel Function and Molecular Structure of Brush Border Membrane Peptide/H+ Symporters , 1996, The Journal of Membrane Biology.

[19]  V. Ganapathy,et al.  Differential Recognition of β-Lactam Antibiotics by Intestinal and Renal Peptide Transporters, PEPT 1 and PEPT 2 (*) , 1995, The Journal of Biological Chemistry.

[20]  T. Abe,et al.  Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. , 2001, The Journal of pharmacology and experimental therapeutics.

[21]  Y. Sai,et al.  Carrier-mediated lung distribution of HSR-903, a new quinolone antibacterial agent. , 1999, The Journal of pharmacology and experimental therapeutics.

[22]  A. Guo,et al.  Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir. , 1998, Biochemical and biophysical research communications.

[23]  D. Groneberg,et al.  Localization of the peptide transporter PEPT2 in the lung: implications for pulmonary oligopeptide uptake. , 2001, The American journal of pathology.

[24]  A. Tsuji Tissue selective drug delivery utilizing carrier-mediated transport systems. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[25]  R. Vaughan-Jones,et al.  Peptide Mimics as Substrates for the Intestinal Peptide Transporter* , 1998, The Journal of Biological Chemistry.

[26]  Cuiping Chen,et al.  P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[27]  T. Nakanishi,et al.  Cancer cell‐targeted drug delivery utilizing oligopeptide transport activity , 2000, International journal of cancer.

[28]  V. Ganapathy,et al.  Na+ - and Cl- -coupled active transport of nitric oxide synthase inhibitors via amino acid transport system B(0,+). , 2001, The Journal of clinical investigation.

[29]  H Ahlbrecht,et al.  Minimal Molecular Determinants of Substrates for Recognition by the Intestinal Peptide Transporter* , 1998, The Journal of Biological Chemistry.

[30]  J. Nezu,et al.  Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. , 1999, The Journal of pharmacology and experimental therapeutics.

[31]  Yuichi Sugiyama,et al.  Impact of Drug Transporter Studies on Drug Discovery and Development , 2003, Pharmacological Reviews.

[32]  T. Nakanishi,et al.  Carrier-mediated transport of oligopeptides in the human fibrosarcoma cell line HT1080. , 1997, Cancer research.

[33]  B. Hirst,et al.  The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[34]  V. Ganapathy,et al.  Transport of Amino Acid-Based Prodrugs by the Na+- and Cl--Coupled Amino Acid Transporter ATB0,+ and Expression of the Transporter in Tissues Amenable for Drug Delivery , 2004, Journal of Pharmacology and Experimental Therapeutics.

[35]  T. Nakanishi,et al.  Immunolocalization and pharmacological relevance of oligopeptide transporter PepT1 in intestinal absorption of β‐lactam antibiotics , 1996, FEBS letters.

[36]  W. Sadee,et al.  An oligopeptide transporter is expressed at high levels in the pancreatic carcinoma cell lines AsPc-1 and Capan-2. , 1998, Cancer research.

[37]  K. Chung,et al.  Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung , 2002, Thorax.

[38]  G R Wilkinson,et al.  OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[39]  Y. Sai,et al.  Blood-Brain Barrier Transport of H1-Antagonist Ebastine and its Metabolite Carebastine , 2000, Journal of drug targeting.

[40]  T. Terasaki,et al.  Structure-tissue distribution relationship based on physiological pharmacokinetics for NY-198, a new antimicrobial agent, and the related pyridonecarboxylic acids. , 1988, Drug metabolism and disposition: the biological fate of chemicals.

[41]  H. Saito,et al.  Functional expression of novel peptide transporter in renal basolateral membranes. , 2000, American journal of physiology. Renal physiology.

[42]  V Ganapathy,et al.  Improvement of L-dopa absorption by dipeptidyl derivation, utilizing peptide transporter PepT1. , 1998, Journal of pharmaceutical sciences.

[43]  L Landmann,et al.  Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. , 2001, Gastroenterology.

[44]  M. Brandsch,et al.  The intestinal H+/peptide symporter PEPT1: structure-affinity relationships. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[45]  K. Giacomini,et al.  Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. , 2001, Journal of pharmaceutical sciences.

[46]  M. Sugawara,et al.  Uptake of dipeptide and beta-lactam antibiotics by the basolateral membrane vesicles prepared from rat kidney. , 2003, Biochimica et biophysica acta.

[47]  V. Ganapathy,et al.  Transport of D-serine via the amino acid transporter ATB(0,+) expressed in the colon. , 2002, Biochemical and biophysical research communications.

[48]  A. Seelig,et al.  Structure-activity relationship of P-glycoprotein substrates and modifiers. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[49]  I. Tamai,et al.  Transporter-mediated permeation of drugs across the blood-brain barrier. , 2000, Journal of pharmaceutical sciences.

[50]  J. Nezu,et al.  Functional Characterization of pH-Sensitive Organic Anion Transporting Polypeptide OATP-B in Human , 2004, Journal of Pharmacology and Experimental Therapeutics.

[51]  B. Brodin,et al.  Di/tri-peptide transporters as drug delivery targets: regulation of transport under physiological and patho-physiological conditions. , 2003, Current drug targets.

[52]  A. Schinkel,et al.  Pharmacological and Physiological Functions of the Polyspecific Organic Cation Transporters: OCT1, 2, and 3 (SLC22A1-3) , 2004, Journal of Pharmacology and Experimental Therapeutics.

[53]  J. Nezu,et al.  Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. , 1999, The Journal of pharmacology and experimental therapeutics.

[54]  Y. Sai,et al.  Delivery of Peptide Drugs to the Brain by Adenovirus-Mediated Heterologous Expression of Human Oligopeptide Transporter at the Blood-Brain Barrier , 2003, Journal of Pharmacology and Experimental Therapeutics.

[55]  T. Terasaki,et al.  Carrier-Mediated Transport of H1-Antagonist at the Blood-Brain Barrier: A Common Transport System of H1-Antagonists and Lipophilic Basic Drugs , 1994, Pharmaceutical Research.

[56]  N. Okamura,et al.  New findings in pharmacological effects induced by antihistamines: from PET studies to knock‐out mice , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[57]  S. Frokjaer,et al.  Intestinal solute carriers: an overview of trends and strategies for improving oral drug absorption. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[58]  González Ma,et al.  Pharmacokinetic overview of oral second-generation H1 antihistamines. , 1998 .

[59]  Y. Kanai,et al.  Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. , 1999, American journal of physiology. Renal physiology.

[60]  V. Ganapathy,et al.  Na+- and Cl--coupled active transport of carnitine by the amino acid transporter ATB(0,+) from mouse colon expressed in HRPE cells and Xenopus oocytes. , 2001, The Journal of physiology.

[61]  Akira Tsuji,et al.  Carrier-Mediated Intestinal Transport of Drugs , 1996, Pharmaceutical Research.

[62]  T. Ishikawa,et al.  The genetic polymorphism of drug transporters: functional analysis approaches. , 2004, Pharmacogenomics.

[63]  M. Hediger,et al.  Differential Recognition of ACE Inhibitors in Xenopus Laevis Oocytes Expressing Rat PEPT1 and PEPT2 , 2000, Pharmaceutical Research.

[64]  V. Ganapathy,et al.  Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. , 1998, Biochemical and biophysical research communications.