Drug Transport and Targeting

Oh, Doo-Man; Han, Hyo-Kyung; Amidon, Gordon L.

doi:10.1007/0-306-46812-3_3

Cited by 51 publications

(44 citation statements)

References 136 publications

(112 reference statements)

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“…The therapeutic use of peptide-based pharmaceuticals for many disorders has been the focus of numerous papers (1)(2)(3)(4)(5)(6). Peptides and peptide-based agents, due largely to multiple side chain functionalities, tend to be polar molecules that do not readily traverse biological barriers via passive diffusion (1,(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

“…Peptides and peptide-based agents, due largely to multiple side chain functionalities, tend to be polar molecules that do not readily traverse biological barriers via passive diffusion (1,(7)(8)(9)(10)(11). In the past several years, considerable work has been performed to explore the active peptide transporters that are known to facilitate peptide transport (5,12,13). Several human small oligopeptide transporters are now known, including peptide transporter 1 (PepT1) and human intestinal peptide transporter 1 (HPT1) (5,(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

“…In the past several years, considerable work has been performed to explore the active peptide transporters that are known to facilitate peptide transport (5,12,13). Several human small oligopeptide transporters are now known, including peptide transporter 1 (PepT1) and human intestinal peptide transporter 1 (HPT1) (5,(14)(15)(16). PepT1 belongs to a superfamily known as proton oligopeptide transporter (POT), where all the known peptide transporters, with the exception of HPT1 (a cadherin family member), are grouped (13,27).…”

Section: Introductionmentioning

confidence: 99%

“…PepT1 belongs to a superfamily known as proton oligopeptide transporter (POT), where all the known peptide transporters, with the exception of HPT1 (a cadherin family member), are grouped (13,27). Of these transporters, PepT1 has gained the most focus and has been theorized to be the predominant peptide transporter in the GIT (1,5,17,18). The focus is on PepT1 because it was the first peptide transporter characterized and because of its high expression in the rat GIT and Caco-2 cell culture model, a human colon-derived adenocarcinoma cell line that has been widely used as an in vitro model of the gastrointestinal enterocytes (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

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Spatial expression patterns of peptide transporters in the human and rat gastrointestinal tracts, Caco-2 In Vitro cell culture model, and multiple human tissues

et al. 2001

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This study sought to identify the spatial patterns of expression of peptide transporter 1 (PepT1), peptide transporter 3 (PTR3), peptide/histidine transporter 1 (PHT1), and the human peptide transporter 1 (HPT-1) mRNA in complementary DNA (cDNA) libraries of the human and rat gastrointestinal tracts (GIT), Caco-2 in vitro cell culture model, and in a human multiple tissue panel. Human PTR3 and PHT1 are putative peptide transporters recently discovered. Using sequencespecific primers designed to amplify regions of PepT1, PTR3, PHT1, and HPT-1, we were able to identify the expression of mRNA for each of these transporters in human cDNA panels (Clontech, Palo Alto, CA), the rat GIT, and in Caco-2 cDNA libraries by the polymerase chain reaction (PCR) and Southern Blot analysis. These studies suggest that in the human GIT, PepT1 appears to be localized predominantly in the duodenum, with decreasing expression in the jejunum and ileum. In contrast, PTR3 and HPT-1 were widely expressed in the human GIT, with predominant expression in the different regions of the colon. PHT1 appeared to be expressed in low levels throughout the human GI tract. Interestingly, the mRNAs for all 4 peptide transporters were expressed in Caco-2 cells throughout 30 days of culture. PepT1, PTR3, PHT1, and HPT-1 were also widely expressed in the rat GIT. Human tissue cDNA panel screening suggests that PTR3 and PHT1 are more uniformly expressed, whereas PepT1 and HPT-1 demonstrated sitespecific expression. These results suggest that PepT1, PTR3, PHT1, and HPT-1 all may act to facilitate the diffusion of peptides and peptide-based pharmaceuticals in the GIT. PTR3, PHT1, and HPT-1 expressions in Caco-2 cell monolayers strongly suggest that their function needs to be further elucidated and their contribution to peptide transport not ignored. Taken together, these results demonstrate the potential for molecular biological characterization in localizing active transporter systems that can potentially be targeted for enhancing the absorption of peptide-based pharmaceuticals.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Spatial expression patterns of peptide transporters in the human and rat gastrointestinal tracts, Caco-2 In Vitro cell culture model, and multiple human tissues

et al. 2001

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“…One of the major problems is the poor permeability through the intestinal mucosa. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the risk of toxic effects), controlling the elimination process, and improving oral bioavailability [21,22]. Intestinal PEPT1 has been utilized to improve the intestinal absorption of poorly absorbed and pharmacologically active agents by chemically converting them to substrates for PEPT1 [5,23].…”

Section: Discussionmentioning

confidence: 99%

Purification by p-aminobenzoic acid (PABA)-affinity chromatography and the functional reconstitution of the nateglinide/H+ cotransport system in the rat intestinal brush-border membrane

Saito¹,

Itagaki²,

Kubo³

et al. 2006

Biochemical and Biophysical Research Communications

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(−)-N-(trans-4-Isopropylcyclohexanecarbonyl)-d-phenylalanine (nateglinide) is a novel oral hypoglycemic agent possessing a peptide-type bond and a carboxyl group in its structure. Recently, we have shown that nateglinide transport occurs via the ceftibuten/H+ cotransport system, which is distinct from PepT1, and that the fluorescein/H+ cotransport system is involved in the uptake of nateglinide. The aim of this study was to characterize the functional properties of the intestinal nateglinide transporter. In the first part of this study, we demonstrated that the ceftibuten/H+ cotransport system is identical to the fluorescein/H+ cotransport system. We succeeded in purification of the nateglinide transporter from brush-border membranes of the rat small intestine using p-aminobenzoic acid (PABA)-affinity chromatography. We then investigated the functional properties of the nateglinide transporter using proteoliposomes prepared from the PABA-affinity chromatography elute. We demonstrated that nateglinide, ceftibuten, and fluorescein are transported by the same transporter in the intestine

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Membrane Transport Proteins and Drug Transport

Swaan

2003

Burger's Medicinal Chemistry and Drug Discovery

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To exert their intended therapeutic goal, drugs need to cross epithelial barriers to reach their site of action. Transport proteins have critical physiological roles in nutrient absorption and transport of endogenous compounds. These systems can serve as useful pharmacological targets and may be used as a mechanism to increase drug absorption. However, we have little understanding of these proteins at the molecular level because of the absence of high resolution crystal structures. Numerous efforts have been made to characterize the P‐glycoprotein efflux pump, the peptide transporter PepT1, and the apical sodium‐dependent transporter, which are important not only for their native transporter function but also as drug targets to increase absorption and bioactivity. In vitro and computational approaches have been applied to gain some insight into these transporters with some success. This represents an opportunity for optimizing molecules as substrates for the solute transporters and providing a further screening system for drug discovery. Clearly the future growth in knowledge of transporter function will be led by integrated in vitro and in silico approaches.

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Drug Transport and Targeting

Cited by 51 publications

References 136 publications

Spatial expression patterns of peptide transporters in the human and rat gastrointestinal tracts, Caco-2 In Vitro cell culture model, and multiple human tissues

Spatial expression patterns of peptide transporters in the human and rat gastrointestinal tracts, Caco-2 In Vitro cell culture model, and multiple human tissues

Purification by p-aminobenzoic acid (PABA)-affinity chromatography and the functional reconstitution of the nateglinide/H+ cotransport system in the rat intestinal brush-border membrane

Membrane Transport Proteins and Drug Transport

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