Intestinal delivery in a long-chain fatty acid formulation enables lymphatic transport and systemic exposure of orlistat
[Display omitted] Orlistat is a pancreatic lipase (PL) inhibitor that inhibits dietary lipid absorption and is used to treat obesity. The oral bioavailability of orlistat is considered zero after administration in standard formulations. This is advantageous in the treatment of obesity. However, if o...
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| Veröffentlicht in: | International journal of pharmaceutics 2021-03, Vol.596, p.120247-120247, Article 120247 |
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| container_title | International journal of pharmaceutics |
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| creator | Lee, Given Han, Sifei Lu, Zijun Hong, Jiwon Phillips, Anthony R.J. Windsor, John A. Porter, Christopher J.H. Trevaskis, Natalie L. |
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Orlistat is a pancreatic lipase (PL) inhibitor that inhibits dietary lipid absorption and is used to treat obesity. The oral bioavailability of orlistat is considered zero after administration in standard formulations. This is advantageous in the treatment of obesity. However, if orlistat absorption could be improved it has the potential to treat diseases such as acute and critical illnesses where PL transport to the systemic circulation via gut lymph promotes organ failure. Orlistat is highly lipophilic and may associate with intestinal lipid absorption pathways into lymph. Here we investigate the potential to improve orlistat lymph and systemic uptake through intestinal administration in lipid formulations (LFs). The effect of lipid type, lipid dose, orlistat dose, and infusion time on lymph and systemic availability of orlistat was investigated. After administration in all LFs, orlistat concentrations in lymph were greater than in plasma, suggesting direct transport via lymph. Lymph and plasma orlistat derivative concentrations were ~8-fold greater after administration in a long-chain fatty acid (LC-FA) compared to a lipid-free, LC triglyceride (LC-TG) or medium-chain FA (MC-FA) formulation. Overall, administration of orlistat in a LC-FA formulation promotes lymph and systemic uptake which may enable treatment of diseases associated with elevated systemic PL activity. |
| doi_str_mv | 10.1016/j.ijpharm.2021.120247 |
| format | Article |
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Orlistat is a pancreatic lipase (PL) inhibitor that inhibits dietary lipid absorption and is used to treat obesity. The oral bioavailability of orlistat is considered zero after administration in standard formulations. This is advantageous in the treatment of obesity. However, if orlistat absorption could be improved it has the potential to treat diseases such as acute and critical illnesses where PL transport to the systemic circulation via gut lymph promotes organ failure. Orlistat is highly lipophilic and may associate with intestinal lipid absorption pathways into lymph. Here we investigate the potential to improve orlistat lymph and systemic uptake through intestinal administration in lipid formulations (LFs). The effect of lipid type, lipid dose, orlistat dose, and infusion time on lymph and systemic availability of orlistat was investigated. After administration in all LFs, orlistat concentrations in lymph were greater than in plasma, suggesting direct transport via lymph. Lymph and plasma orlistat derivative concentrations were ~8-fold greater after administration in a long-chain fatty acid (LC-FA) compared to a lipid-free, LC triglyceride (LC-TG) or medium-chain FA (MC-FA) formulation. Overall, administration of orlistat in a LC-FA formulation promotes lymph and systemic uptake which may enable treatment of diseases associated with elevated systemic PL activity.</description><identifier>ISSN: 0378-5173</identifier><identifier>EISSN: 1873-3476</identifier><identifier>DOI: 10.1016/j.ijpharm.2021.120247</identifier><identifier>PMID: 33486039</identifier><language>eng</language><publisher>AMSTERDAM: Elsevier B.V</publisher><subject>Drug Delivery ; Fatty Acid ; Life Sciences & Biomedicine ; Lipase inhibitor ; Lipid Formulation ; Lymphatic ; Orlistat ; Pharmacology & Pharmacy ; Science & Technology</subject><ispartof>International journal of pharmaceutics, 2021-03, Vol.596, p.120247-120247, Article 120247</ispartof><rights>2021</rights><rights>Copyright © 2021. Published by Elsevier B.V.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>10</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000620711800028</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c478t-9e829c5efcd6d2b9fec9fcafeb236d0f537472dec4df825e1d03fc0c8030ae693</citedby><cites>FETCH-LOGICAL-c478t-9e829c5efcd6d2b9fec9fcafeb236d0f537472dec4df825e1d03fc0c8030ae693</cites><orcidid>0000-0001-6143-5866 ; 0000-0003-0936-3281 ; 0000-0001-7433-3711 ; 0000-0001-9538-549X ; 0000-0003-3474-7551</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ijpharm.2021.120247$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,782,786,3552,27931,27932,39265,46002</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33486039$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Given</creatorcontrib><creatorcontrib>Han, Sifei</creatorcontrib><creatorcontrib>Lu, Zijun</creatorcontrib><creatorcontrib>Hong, Jiwon</creatorcontrib><creatorcontrib>Phillips, Anthony R.J.</creatorcontrib><creatorcontrib>Windsor, John A.</creatorcontrib><creatorcontrib>Porter, Christopher J.H.</creatorcontrib><creatorcontrib>Trevaskis, Natalie L.</creatorcontrib><title>Intestinal delivery in a long-chain fatty acid formulation enables lymphatic transport and systemic exposure of orlistat</title><title>International journal of pharmaceutics</title><addtitle>INT J PHARMACEUT</addtitle><addtitle>Int J Pharm</addtitle><description>[Display omitted]
Orlistat is a pancreatic lipase (PL) inhibitor that inhibits dietary lipid absorption and is used to treat obesity. The oral bioavailability of orlistat is considered zero after administration in standard formulations. This is advantageous in the treatment of obesity. However, if orlistat absorption could be improved it has the potential to treat diseases such as acute and critical illnesses where PL transport to the systemic circulation via gut lymph promotes organ failure. Orlistat is highly lipophilic and may associate with intestinal lipid absorption pathways into lymph. Here we investigate the potential to improve orlistat lymph and systemic uptake through intestinal administration in lipid formulations (LFs). The effect of lipid type, lipid dose, orlistat dose, and infusion time on lymph and systemic availability of orlistat was investigated. After administration in all LFs, orlistat concentrations in lymph were greater than in plasma, suggesting direct transport via lymph. Lymph and plasma orlistat derivative concentrations were ~8-fold greater after administration in a long-chain fatty acid (LC-FA) compared to a lipid-free, LC triglyceride (LC-TG) or medium-chain FA (MC-FA) formulation. Overall, administration of orlistat in a LC-FA formulation promotes lymph and systemic uptake which may enable treatment of diseases associated with elevated systemic PL activity.</description><subject>Drug Delivery</subject><subject>Fatty Acid</subject><subject>Life Sciences & Biomedicine</subject><subject>Lipase inhibitor</subject><subject>Lipid Formulation</subject><subject>Lymphatic</subject><subject>Orlistat</subject><subject>Pharmacology & Pharmacy</subject><subject>Science & Technology</subject><issn>0378-5173</issn><issn>1873-3476</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><recordid>eNqNkUtv1DAURiMEokPhJ4C8REIZ_EhiZ4XQiEelSmxgbTn2NfXIsQfbKc2_x22GbmHjl85n-57bNK8J3hNMhvfHvTueblSa9xRTsid17PiTZkcEZy3r-PC02WHGRdsTzi6aFzkfMcYDJex5c8FYJwbMxl1zdxUK5OKC8siAd7eQVuQCUsjH8LPVN6purCplRUo7g2xM8-JVcTEgCGrykJFf5_qT4jQqSYV8iqkgFQzKay4w12O4O8W8JEDRopi8y0WVl80zq3yGV-f5svnx-dP3w9f2-tuXq8PH61Z3XJR2BEFH3YPVZjB0Gi3o0WplYaJsMNj2jHecGtCdsYL2QAxmVmMtMMMKhpFdNm-3e08p_lpqqXJ2WYP3KkBcsqSdwLzruegq2m-oTjHnBFaekptVWiXB8l66PMqzdHkvXW7Sa-7N-YllmsE8pv5arsC7DfgNU7RZOwgaHrGHtmBOiKgrKiot_p8-uPLQjENcQqnRD1sUqtFbB0me48Yl0EWa6P5Ryx8l-Low</recordid><startdate>20210301</startdate><enddate>20210301</enddate><creator>Lee, Given</creator><creator>Han, Sifei</creator><creator>Lu, Zijun</creator><creator>Hong, Jiwon</creator><creator>Phillips, Anthony R.J.</creator><creator>Windsor, John A.</creator><creator>Porter, Christopher J.H.</creator><creator>Trevaskis, Natalie L.</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6143-5866</orcidid><orcidid>https://orcid.org/0000-0003-0936-3281</orcidid><orcidid>https://orcid.org/0000-0001-7433-3711</orcidid><orcidid>https://orcid.org/0000-0001-9538-549X</orcidid><orcidid>https://orcid.org/0000-0003-3474-7551</orcidid></search><sort><creationdate>20210301</creationdate><title>Intestinal delivery in a long-chain fatty acid formulation enables lymphatic transport and systemic exposure of orlistat</title><author>Lee, Given ; Han, Sifei ; Lu, Zijun ; Hong, Jiwon ; Phillips, Anthony R.J. ; Windsor, John A. ; Porter, Christopher J.H. ; Trevaskis, Natalie L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-9e829c5efcd6d2b9fec9fcafeb236d0f537472dec4df825e1d03fc0c8030ae693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Drug Delivery</topic><topic>Fatty Acid</topic><topic>Life Sciences & Biomedicine</topic><topic>Lipase inhibitor</topic><topic>Lipid Formulation</topic><topic>Lymphatic</topic><topic>Orlistat</topic><topic>Pharmacology & Pharmacy</topic><topic>Science & Technology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Given</creatorcontrib><creatorcontrib>Han, Sifei</creatorcontrib><creatorcontrib>Lu, Zijun</creatorcontrib><creatorcontrib>Hong, Jiwon</creatorcontrib><creatorcontrib>Phillips, Anthony R.J.</creatorcontrib><creatorcontrib>Windsor, John A.</creatorcontrib><creatorcontrib>Porter, Christopher J.H.</creatorcontrib><creatorcontrib>Trevaskis, Natalie L.</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of pharmaceutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Given</au><au>Han, Sifei</au><au>Lu, Zijun</au><au>Hong, Jiwon</au><au>Phillips, Anthony R.J.</au><au>Windsor, John A.</au><au>Porter, Christopher J.H.</au><au>Trevaskis, Natalie L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intestinal delivery in a long-chain fatty acid formulation enables lymphatic transport and systemic exposure of orlistat</atitle><jtitle>International journal of pharmaceutics</jtitle><stitle>INT J PHARMACEUT</stitle><addtitle>Int J Pharm</addtitle><date>2021-03-01</date><risdate>2021</risdate><volume>596</volume><spage>120247</spage><epage>120247</epage><pages>120247-120247</pages><artnum>120247</artnum><issn>0378-5173</issn><eissn>1873-3476</eissn><abstract>[Display omitted]
Orlistat is a pancreatic lipase (PL) inhibitor that inhibits dietary lipid absorption and is used to treat obesity. The oral bioavailability of orlistat is considered zero after administration in standard formulations. This is advantageous in the treatment of obesity. However, if orlistat absorption could be improved it has the potential to treat diseases such as acute and critical illnesses where PL transport to the systemic circulation via gut lymph promotes organ failure. Orlistat is highly lipophilic and may associate with intestinal lipid absorption pathways into lymph. Here we investigate the potential to improve orlistat lymph and systemic uptake through intestinal administration in lipid formulations (LFs). The effect of lipid type, lipid dose, orlistat dose, and infusion time on lymph and systemic availability of orlistat was investigated. After administration in all LFs, orlistat concentrations in lymph were greater than in plasma, suggesting direct transport via lymph. Lymph and plasma orlistat derivative concentrations were ~8-fold greater after administration in a long-chain fatty acid (LC-FA) compared to a lipid-free, LC triglyceride (LC-TG) or medium-chain FA (MC-FA) formulation. Overall, administration of orlistat in a LC-FA formulation promotes lymph and systemic uptake which may enable treatment of diseases associated with elevated systemic PL activity.</abstract><cop>AMSTERDAM</cop><pub>Elsevier B.V</pub><pmid>33486039</pmid><doi>10.1016/j.ijpharm.2021.120247</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-6143-5866</orcidid><orcidid>https://orcid.org/0000-0003-0936-3281</orcidid><orcidid>https://orcid.org/0000-0001-7433-3711</orcidid><orcidid>https://orcid.org/0000-0001-9538-549X</orcidid><orcidid>https://orcid.org/0000-0003-3474-7551</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Drug Delivery Fatty Acid Life Sciences & Biomedicine Lipase inhibitor Lipid Formulation Lymphatic Orlistat Pharmacology & Pharmacy Science & Technology |
| title | Intestinal delivery in a long-chain fatty acid formulation enables lymphatic transport and systemic exposure of orlistat |
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