Intestinal secretion of indoxyl sulfate as a possible compensatory excretion pathway in chronic kidney disease
Indoxyl sulfate (IS) is a protein‐bound uremic toxin that progressively accumulates in plasma during chronic kidney disease (CKD), and its accumulation is associated with the progression of CKD. This study examined the intestinal secretion of IS using in situ single‐pass intestinal perfusion in a ra...
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| Veröffentlicht in: | Biopharmaceutics & drug disposition 2018-07, Vol.39 (7), p.328-334 |
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| creator | Morimoto, Kaori Tominaga, Yuuta Agatsuma, Yuta Miyamoto, Masanari Kashiwagura, Shota Takahashi, Akira Sano, Yoshimi Yano, Kentaro Kakinuma, Chihaya Ogihara, Takuo Tomita, Mikio |
| description | Indoxyl sulfate (IS) is a protein‐bound uremic toxin that progressively accumulates in plasma during chronic kidney disease (CKD), and its accumulation is associated with the progression of CKD. This study examined the intestinal secretion of IS using in situ single‐pass intestinal perfusion in a rat model of renal insufficiency, MRP2‐ and BCRP‐overexpressing Sf9 membrane vesicles, and Caco‐2 cell monolayers. An in situ single‐pass perfusion study in CKD model rats demonstrated that a small amount of IS is secreted into intestinal lumen after iv administration of IS, and the clearance increased AUC‐dependently. An excess amount of IS (3 mm) partially inhibited the MRP2‐ and BCRP‐mediated uptake of specific fluorescent substrates, CDCF and Lucifer yellow, respectively, into the membrane vesicles, although IS was not taken up at a physiological concentration, 10 μm. In the Caco‐2 cell monolayers, the IS transport was higher in the absorptive direction than in the secretory direction (p |
| doi_str_mv | 10.1002/bdd.2149 |
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This study examined the intestinal secretion of IS using in situ single‐pass intestinal perfusion in a rat model of renal insufficiency, MRP2‐ and BCRP‐overexpressing Sf9 membrane vesicles, and Caco‐2 cell monolayers. An in situ single‐pass perfusion study in CKD model rats demonstrated that a small amount of IS is secreted into intestinal lumen after iv administration of IS, and the clearance increased AUC‐dependently. An excess amount of IS (3 mm) partially inhibited the MRP2‐ and BCRP‐mediated uptake of specific fluorescent substrates, CDCF and Lucifer yellow, respectively, into the membrane vesicles, although IS was not taken up at a physiological concentration, 10 μm. In the Caco‐2 cell monolayers, the IS transport was higher in the absorptive direction than in the secretory direction (p < 0.05). p‐Aminohippuric acid (PAH) strongly inhibited IS transport in both directions (absorptive, p = 0.142; secretory, p < 0.01). Given that the blood IS levels are much higher than those in the intestinal lumen, it is possible that this unknown PAH‐sensitive system contributes to the intestinal IS secretion. Although in situ inhibition study is needed to confirm that this unknown transporter mediates the in vivo intestinal secretion of IS, we speculate that this unknown active efflux system works as a compensatory excretion pathway for excess organic anions such as IS especially in end‐stage renal disease.</description><identifier>ISSN: 0142-2782</identifier><identifier>EISSN: 1099-081X</identifier><identifier>DOI: 10.1002/bdd.2149</identifier><identifier>PMID: 29975986</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Absorptivity ; Anions ; Bile ; chronic kidney disease ; Excretion ; indoxyl sulfate ; intestinal secretion ; Intestine ; Kidney diseases ; Kidneys ; Membrane vesicles ; Perfusion ; Renal insufficiency ; Rodents ; Secretion ; Sulfates ; transport ; Vesicles</subject><ispartof>Biopharmaceutics & drug disposition, 2018-07, Vol.39 (7), p.328-334</ispartof><rights>2018 John Wiley & Sons, Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4159-249242ba7dc067444b089ea8c1ebc5b78752e69f81889d590aee4b5e057b6ccc3</citedby><cites>FETCH-LOGICAL-c4159-249242ba7dc067444b089ea8c1ebc5b78752e69f81889d590aee4b5e057b6ccc3</cites><orcidid>0000-0001-5328-8843</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fbdd.2149$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fbdd.2149$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1416,27923,27924,45573,45574</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29975986$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morimoto, Kaori</creatorcontrib><creatorcontrib>Tominaga, Yuuta</creatorcontrib><creatorcontrib>Agatsuma, Yuta</creatorcontrib><creatorcontrib>Miyamoto, Masanari</creatorcontrib><creatorcontrib>Kashiwagura, Shota</creatorcontrib><creatorcontrib>Takahashi, Akira</creatorcontrib><creatorcontrib>Sano, Yoshimi</creatorcontrib><creatorcontrib>Yano, Kentaro</creatorcontrib><creatorcontrib>Kakinuma, Chihaya</creatorcontrib><creatorcontrib>Ogihara, Takuo</creatorcontrib><creatorcontrib>Tomita, Mikio</creatorcontrib><title>Intestinal secretion of indoxyl sulfate as a possible compensatory excretion pathway in chronic kidney disease</title><title>Biopharmaceutics & drug disposition</title><addtitle>Biopharm Drug Dispos</addtitle><description>Indoxyl sulfate (IS) is a protein‐bound uremic toxin that progressively accumulates in plasma during chronic kidney disease (CKD), and its accumulation is associated with the progression of CKD. This study examined the intestinal secretion of IS using in situ single‐pass intestinal perfusion in a rat model of renal insufficiency, MRP2‐ and BCRP‐overexpressing Sf9 membrane vesicles, and Caco‐2 cell monolayers. An in situ single‐pass perfusion study in CKD model rats demonstrated that a small amount of IS is secreted into intestinal lumen after iv administration of IS, and the clearance increased AUC‐dependently. An excess amount of IS (3 mm) partially inhibited the MRP2‐ and BCRP‐mediated uptake of specific fluorescent substrates, CDCF and Lucifer yellow, respectively, into the membrane vesicles, although IS was not taken up at a physiological concentration, 10 μm. In the Caco‐2 cell monolayers, the IS transport was higher in the absorptive direction than in the secretory direction (p < 0.05). p‐Aminohippuric acid (PAH) strongly inhibited IS transport in both directions (absorptive, p = 0.142; secretory, p < 0.01). Given that the blood IS levels are much higher than those in the intestinal lumen, it is possible that this unknown PAH‐sensitive system contributes to the intestinal IS secretion. Although in situ inhibition study is needed to confirm that this unknown transporter mediates the in vivo intestinal secretion of IS, we speculate that this unknown active efflux system works as a compensatory excretion pathway for excess organic anions such as IS especially in end‐stage renal disease.</description><subject>Absorptivity</subject><subject>Anions</subject><subject>Bile</subject><subject>chronic kidney disease</subject><subject>Excretion</subject><subject>indoxyl sulfate</subject><subject>intestinal secretion</subject><subject>Intestine</subject><subject>Kidney diseases</subject><subject>Kidneys</subject><subject>Membrane vesicles</subject><subject>Perfusion</subject><subject>Renal insufficiency</subject><subject>Rodents</subject><subject>Secretion</subject><subject>Sulfates</subject><subject>transport</subject><subject>Vesicles</subject><issn>0142-2782</issn><issn>1099-081X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kU1LxDAQhoMouq6Cv0ACXrxUkzRtk6PfCoIXBW8lSacY7SY1adH-e7OuHyB4GhieeWDeF6E9So4oIexYN80Ro1yuoRklUmZE0Md1NCOUs4xVgm2h7RifCSElpXQTbTEpq0KKcobcjRsgDtapDkcwAQbrHfYttq7x71Najl2rBsAqYoV7H6PVHWDjFz24qAYfJgzv33e9Gp7e1JSOsXkK3lmDX2zjYMKNjaAi7KCNVnURdr_mHD1cXtyfXWe3d1c3Zye3meG0kBnjknGmVdUYUlacc02EBCUMBW0KXYmqYFDKVlAhZFNIogC4LoAUlS6NMfkcHa68ffCvY3qwXthooOuUAz_GmpGy5FWR5zShB3_QZz-GlMeSkiwXkubiV2hCyiBAW_fBLlSYakrqZQd16qBedpDQ_S_hqBfQ_IDfoScgWwFvtoPpX1F9en7-KfwAZ-eRAA</recordid><startdate>201807</startdate><enddate>201807</enddate><creator>Morimoto, Kaori</creator><creator>Tominaga, Yuuta</creator><creator>Agatsuma, Yuta</creator><creator>Miyamoto, Masanari</creator><creator>Kashiwagura, Shota</creator><creator>Takahashi, Akira</creator><creator>Sano, Yoshimi</creator><creator>Yano, Kentaro</creator><creator>Kakinuma, Chihaya</creator><creator>Ogihara, Takuo</creator><creator>Tomita, Mikio</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5328-8843</orcidid></search><sort><creationdate>201807</creationdate><title>Intestinal secretion of indoxyl sulfate as a possible compensatory excretion pathway in chronic kidney disease</title><author>Morimoto, Kaori ; Tominaga, Yuuta ; Agatsuma, Yuta ; Miyamoto, Masanari ; Kashiwagura, Shota ; Takahashi, Akira ; Sano, Yoshimi ; Yano, Kentaro ; Kakinuma, Chihaya ; Ogihara, Takuo ; Tomita, Mikio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4159-249242ba7dc067444b089ea8c1ebc5b78752e69f81889d590aee4b5e057b6ccc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Absorptivity</topic><topic>Anions</topic><topic>Bile</topic><topic>chronic kidney disease</topic><topic>Excretion</topic><topic>indoxyl sulfate</topic><topic>intestinal secretion</topic><topic>Intestine</topic><topic>Kidney diseases</topic><topic>Kidneys</topic><topic>Membrane vesicles</topic><topic>Perfusion</topic><topic>Renal insufficiency</topic><topic>Rodents</topic><topic>Secretion</topic><topic>Sulfates</topic><topic>transport</topic><topic>Vesicles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Morimoto, Kaori</creatorcontrib><creatorcontrib>Tominaga, Yuuta</creatorcontrib><creatorcontrib>Agatsuma, Yuta</creatorcontrib><creatorcontrib>Miyamoto, Masanari</creatorcontrib><creatorcontrib>Kashiwagura, Shota</creatorcontrib><creatorcontrib>Takahashi, Akira</creatorcontrib><creatorcontrib>Sano, Yoshimi</creatorcontrib><creatorcontrib>Yano, Kentaro</creatorcontrib><creatorcontrib>Kakinuma, Chihaya</creatorcontrib><creatorcontrib>Ogihara, Takuo</creatorcontrib><creatorcontrib>Tomita, Mikio</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biopharmaceutics & drug disposition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morimoto, Kaori</au><au>Tominaga, Yuuta</au><au>Agatsuma, Yuta</au><au>Miyamoto, Masanari</au><au>Kashiwagura, Shota</au><au>Takahashi, Akira</au><au>Sano, Yoshimi</au><au>Yano, Kentaro</au><au>Kakinuma, Chihaya</au><au>Ogihara, Takuo</au><au>Tomita, Mikio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intestinal secretion of indoxyl sulfate as a possible compensatory excretion pathway in chronic kidney disease</atitle><jtitle>Biopharmaceutics & drug disposition</jtitle><addtitle>Biopharm Drug Dispos</addtitle><date>2018-07</date><risdate>2018</risdate><volume>39</volume><issue>7</issue><spage>328</spage><epage>334</epage><pages>328-334</pages><issn>0142-2782</issn><eissn>1099-081X</eissn><abstract>Indoxyl sulfate (IS) is a protein‐bound uremic toxin that progressively accumulates in plasma during chronic kidney disease (CKD), and its accumulation is associated with the progression of CKD. This study examined the intestinal secretion of IS using in situ single‐pass intestinal perfusion in a rat model of renal insufficiency, MRP2‐ and BCRP‐overexpressing Sf9 membrane vesicles, and Caco‐2 cell monolayers. An in situ single‐pass perfusion study in CKD model rats demonstrated that a small amount of IS is secreted into intestinal lumen after iv administration of IS, and the clearance increased AUC‐dependently. An excess amount of IS (3 mm) partially inhibited the MRP2‐ and BCRP‐mediated uptake of specific fluorescent substrates, CDCF and Lucifer yellow, respectively, into the membrane vesicles, although IS was not taken up at a physiological concentration, 10 μm. In the Caco‐2 cell monolayers, the IS transport was higher in the absorptive direction than in the secretory direction (p < 0.05). p‐Aminohippuric acid (PAH) strongly inhibited IS transport in both directions (absorptive, p = 0.142; secretory, p < 0.01). Given that the blood IS levels are much higher than those in the intestinal lumen, it is possible that this unknown PAH‐sensitive system contributes to the intestinal IS secretion. Although in situ inhibition study is needed to confirm that this unknown transporter mediates the in vivo intestinal secretion of IS, we speculate that this unknown active efflux system works as a compensatory excretion pathway for excess organic anions such as IS especially in end‐stage renal disease.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>29975986</pmid><doi>10.1002/bdd.2149</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-5328-8843</orcidid></addata></record> |
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| subjects | Absorptivity Anions Bile chronic kidney disease Excretion indoxyl sulfate intestinal secretion Intestine Kidney diseases Kidneys Membrane vesicles Perfusion Renal insufficiency Rodents Secretion Sulfates transport Vesicles |
| title | Intestinal secretion of indoxyl sulfate as a possible compensatory excretion pathway in chronic kidney disease |
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