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The effect of ΔG on the transport and oral absorption of macromolecules
Delta G (ΔG) is the biologically active fragment of Zonula Occludens Toxin (Zot), an absorption enhancer, that reversibly opens the tight junctions of epithelial and endothelial cells in the small intestine and brain. This study evaluates the possible use of ΔG in enhancing the oral bioavailability...
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| Published in: | Journal of pharmaceutical sciences 2004-05, Vol.93 (5), p.1310-1319 |
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| Main Authors: | , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-c4332-d096359ff5a51e33f4268a2b355c58d40bae0ecaaa0e3c080aefc11660431bb83 |
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| cites | cdi_FETCH-LOGICAL-c4332-d096359ff5a51e33f4268a2b355c58d40bae0ecaaa0e3c080aefc11660431bb83 |
| container_end_page | 1319 |
| container_issue | 5 |
| container_start_page | 1310 |
| container_title | Journal of pharmaceutical sciences |
| container_volume | 93 |
| creator | Salama, Noha N. Fasano, Alessio Thakar, Manjusha Eddington, Natalie D. |
| description | Delta G (ΔG) is the biologically active fragment of Zonula Occludens Toxin (Zot), an absorption enhancer, that reversibly opens the tight junctions of epithelial and endothelial cells in the small intestine and brain. This study evaluates the possible use of ΔG in enhancing the oral bioavailability of macromolecules using large paracellular markers as model agents. The transport of [14C]Inulin and [14C]PEG4000 was evaluated across Caco-2 cells with ΔG (0, 100, 180 μg/ml). The apparent permeability coefficients (Papp) were calculated. The in vitro toxicity of ΔG (180 μg/ml) was assessed. Sprague Dawley rats were dosed intraduodenally (ID) with the following treatments: [14C]Inulin or [14C]PEG4000 (30 μci/kg) w/o ΔG (720 μg/kg)/protease inhibitors (PI). Blood was collected and plasma was analyzed for radioactivity. ΔG (180 μg/ml) increased [14C]Inulin and [14C]PEG4000 Papp by 82.6 and 24.4%, respectively, without any toxicity. After ID administration with ΔG/PI, Cmax and AUC were significantly (p |
| doi_str_mv | 10.1002/jps.20052 |
| format | article |
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This study evaluates the possible use of ΔG in enhancing the oral bioavailability of macromolecules using large paracellular markers as model agents. The transport of [14C]Inulin and [14C]PEG4000 was evaluated across Caco-2 cells with ΔG (0, 100, 180 μg/ml). The apparent permeability coefficients (Papp) were calculated. The in vitro toxicity of ΔG (180 μg/ml) was assessed. Sprague Dawley rats were dosed intraduodenally (ID) with the following treatments: [14C]Inulin or [14C]PEG4000 (30 μci/kg) w/o ΔG (720 μg/kg)/protease inhibitors (PI). Blood was collected and plasma was analyzed for radioactivity. ΔG (180 μg/ml) increased [14C]Inulin and [14C]PEG4000 Papp by 82.6 and 24.4%, respectively, without any toxicity. After ID administration with ΔG/PI, Cmax and AUC were significantly (p < 0.05) increased for both Inulin and PEG4000. However, Inulin displayed greater enhancement ratios in vitro and in vivo. This study suggests that ΔG may be used to enhance the oral bioavailability of macromolecules (e.g., proteins) after coadministration through modulation of paracellular transport. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1310–1319, 2004</description><identifier>ISSN: 0022-3549</identifier><identifier>EISSN: 1520-6017</identifier><identifier>DOI: 10.1002/jps.20052</identifier><identifier>PMID: 15067707</identifier><identifier>CODEN: JPMSAE</identifier><language>eng</language><publisher>Hoboken: Elsevier Inc</publisher><subject>Absorption - drug effects ; Absorption - physiology ; absorption enhancer ; Administration, Oral ; Animals ; bioavailability ; Biological and medical sciences ; Biological Transport - drug effects ; Biological Transport - physiology ; Caco-2 Cells ; Cell Survival - drug effects ; Cell Survival - physiology ; Cholera Toxin - administration & dosage ; Cholera Toxin - metabolism ; Drug Evaluation, Preclinical - methods ; General pharmacology ; Humans ; Macromolecular Substances - administration & dosage ; Macromolecular Substances - metabolism ; Male ; Medical sciences ; oral absorption ; Pharmaceutical technology. 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Pharm. Sci</addtitle><description>Delta G (ΔG) is the biologically active fragment of Zonula Occludens Toxin (Zot), an absorption enhancer, that reversibly opens the tight junctions of epithelial and endothelial cells in the small intestine and brain. This study evaluates the possible use of ΔG in enhancing the oral bioavailability of macromolecules using large paracellular markers as model agents. The transport of [14C]Inulin and [14C]PEG4000 was evaluated across Caco-2 cells with ΔG (0, 100, 180 μg/ml). The apparent permeability coefficients (Papp) were calculated. The in vitro toxicity of ΔG (180 μg/ml) was assessed. Sprague Dawley rats were dosed intraduodenally (ID) with the following treatments: [14C]Inulin or [14C]PEG4000 (30 μci/kg) w/o ΔG (720 μg/kg)/protease inhibitors (PI). Blood was collected and plasma was analyzed for radioactivity. ΔG (180 μg/ml) increased [14C]Inulin and [14C]PEG4000 Papp by 82.6 and 24.4%, respectively, without any toxicity. After ID administration with ΔG/PI, Cmax and AUC were significantly (p < 0.05) increased for both Inulin and PEG4000. However, Inulin displayed greater enhancement ratios in vitro and in vivo. This study suggests that ΔG may be used to enhance the oral bioavailability of macromolecules (e.g., proteins) after coadministration through modulation of paracellular transport. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1310–1319, 2004</description><subject>Absorption - drug effects</subject><subject>Absorption - physiology</subject><subject>absorption enhancer</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>bioavailability</subject><subject>Biological and medical sciences</subject><subject>Biological Transport - drug effects</subject><subject>Biological Transport - physiology</subject><subject>Caco-2 Cells</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - physiology</subject><subject>Cholera Toxin - administration & dosage</subject><subject>Cholera Toxin - metabolism</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>General pharmacology</subject><subject>Humans</subject><subject>Macromolecular Substances - administration & dosage</subject><subject>Macromolecular Substances - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>oral absorption</subject><subject>Pharmaceutical technology. Pharmaceutical industry</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Zot</subject><issn>0022-3549</issn><issn>1520-6017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNp10c1O3DAQB3ALgWChHHgBlAuHHgLjOHayx2opS1ergtRtK3GxJs5YNc1uIjt8vQfPxTPhkoX2QE-W7N94NP9h7IDDMQfITq67cJwByGyDjbjMIFXAi002im9ZKmQ-3mG7IVwDgAIpt9kOl6CKAooRO1_8ooSsJdMnrU2eHqdJu0r6eNl7XIWu9X2CqzppPTYJVqH1Xe-iiHaJxrfLtiFz01D4wLYsNoH21-ce-372eTE5T-cX0y-TT_PU5EJkaQ1jJeTYWomSkxA2z1SJWSWkNLKsc6iQgAwiAgkDJSBZw7lSkAteVaXYYx-Hf2PzEDxZ3Xm3RP-gOeg_aeiYhn5JI9rDwXY31ZLqv3I9fgRHa4DBYGPjyMaFf5xSEgREdzK4O9fQw_876tnlt9fW6VDhQk_3bxXof2tViELqn1-nupycXl3OZj80j14MnmJ2t468DsbRylDtfNyNrlv3zoDPPbSXDQ</recordid><startdate>200405</startdate><enddate>200405</enddate><creator>Salama, Noha N.</creator><creator>Fasano, Alessio</creator><creator>Thakar, Manjusha</creator><creator>Eddington, Natalie D.</creator><general>Elsevier Inc</general><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><general>American Pharmaceutical Association</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>200405</creationdate><title>The effect of ΔG on the transport and oral absorption of macromolecules</title><author>Salama, Noha N. ; Fasano, Alessio ; Thakar, Manjusha ; Eddington, Natalie D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4332-d096359ff5a51e33f4268a2b355c58d40bae0ecaaa0e3c080aefc11660431bb83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Absorption - drug effects</topic><topic>Absorption - physiology</topic><topic>absorption enhancer</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>bioavailability</topic><topic>Biological and medical sciences</topic><topic>Biological Transport - drug effects</topic><topic>Biological Transport - physiology</topic><topic>Caco-2 Cells</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - physiology</topic><topic>Cholera Toxin - administration & dosage</topic><topic>Cholera Toxin - metabolism</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>General pharmacology</topic><topic>Humans</topic><topic>Macromolecular Substances - administration & dosage</topic><topic>Macromolecular Substances - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>oral absorption</topic><topic>Pharmaceutical technology. Pharmaceutical industry</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Zot</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Salama, Noha N.</creatorcontrib><creatorcontrib>Fasano, Alessio</creatorcontrib><creatorcontrib>Thakar, Manjusha</creatorcontrib><creatorcontrib>Eddington, Natalie D.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Salama, Noha N.</au><au>Fasano, Alessio</au><au>Thakar, Manjusha</au><au>Eddington, Natalie D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The effect of ΔG on the transport and oral absorption of macromolecules</atitle><jtitle>Journal of pharmaceutical sciences</jtitle><addtitle>J. Pharm. Sci</addtitle><date>2004-05</date><risdate>2004</risdate><volume>93</volume><issue>5</issue><spage>1310</spage><epage>1319</epage><pages>1310-1319</pages><issn>0022-3549</issn><eissn>1520-6017</eissn><coden>JPMSAE</coden><abstract>Delta G (ΔG) is the biologically active fragment of Zonula Occludens Toxin (Zot), an absorption enhancer, that reversibly opens the tight junctions of epithelial and endothelial cells in the small intestine and brain. This study evaluates the possible use of ΔG in enhancing the oral bioavailability of macromolecules using large paracellular markers as model agents. The transport of [14C]Inulin and [14C]PEG4000 was evaluated across Caco-2 cells with ΔG (0, 100, 180 μg/ml). The apparent permeability coefficients (Papp) were calculated. The in vitro toxicity of ΔG (180 μg/ml) was assessed. Sprague Dawley rats were dosed intraduodenally (ID) with the following treatments: [14C]Inulin or [14C]PEG4000 (30 μci/kg) w/o ΔG (720 μg/kg)/protease inhibitors (PI). Blood was collected and plasma was analyzed for radioactivity. ΔG (180 μg/ml) increased [14C]Inulin and [14C]PEG4000 Papp by 82.6 and 24.4%, respectively, without any toxicity. After ID administration with ΔG/PI, Cmax and AUC were significantly (p < 0.05) increased for both Inulin and PEG4000. However, Inulin displayed greater enhancement ratios in vitro and in vivo. This study suggests that ΔG may be used to enhance the oral bioavailability of macromolecules (e.g., proteins) after coadministration through modulation of paracellular transport. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1310–1319, 2004</abstract><cop>Hoboken</cop><pub>Elsevier Inc</pub><pmid>15067707</pmid><doi>10.1002/jps.20052</doi><tpages>10</tpages></addata></record> |
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| ispartof | Journal of pharmaceutical sciences, 2004-05, Vol.93 (5), p.1310-1319 |
| issn | 0022-3549 1520-6017 |
| language | eng |
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| source | Wiley-Blackwell Journals; ScienceDirect Journals |
| subjects | Absorption - drug effects Absorption - physiology absorption enhancer Administration, Oral Animals bioavailability Biological and medical sciences Biological Transport - drug effects Biological Transport - physiology Caco-2 Cells Cell Survival - drug effects Cell Survival - physiology Cholera Toxin - administration & dosage Cholera Toxin - metabolism Drug Evaluation, Preclinical - methods General pharmacology Humans Macromolecular Substances - administration & dosage Macromolecular Substances - metabolism Male Medical sciences oral absorption Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Rats Rats, Sprague-Dawley Zot |
| title | The effect of ΔG on the transport and oral absorption of macromolecules |
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