Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions
The organic anion transporting polypeptide (OATP)2B1 is localized on the basolateral membrane of hepatocytes and is expressed in enterocytes. Based on its distribution pattern and functional similarity to OATP1B-type transporters, OATP2B1 might have a role in the absorption and disposition of a rang...
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Veröffentlicht in: | Drug metabolism and disposition 2020-05, Vol.48 (5), p.419-425 |
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creator | Chen, Mingqing Hu, Shuiying Li, Yang Gibson, Alice A. Fu, Qiang Baker, Sharyn D. Sparreboom, Alex |
description | The organic anion transporting polypeptide (OATP)2B1 is localized on the basolateral membrane of hepatocytes and is expressed in enterocytes. Based on its distribution pattern and functional similarity to OATP1B-type transporters, OATP2B1 might have a role in the absorption and disposition of a range of xenobiotics. Although several prescription drugs, including hydroxymethylglutaryl-coenzyme A-CoA reductase inhibitors (statins) such as fluvastatin, are OATP2B1 substrates in vitro, evidence supporting the in vivo relevance of this transporter remains limited, and most has relied on substrate-inhibitor interactions resulting in altered pharmacokinetic properties of the victim drugs. To address this knowledge deficit, we developed and characterized an Oatp2b1-deficient mouse model and evaluated the impact of this transporter on the absorption and disposition of fluvastatin. Consistent with the intestinal localization of Oatp2b1, we found that the genetic deletion or pharmacological inhibition of Oatp2b1 was associated with decreased absorption of fluvastatin by 2- to 3-fold. The availability of a viable Oatp2b1-deficient mouse model provides an opportunity to unequivocally determine the contribution of this transporter to the absorption and drug-drug interaction potential of drugs.
The current investigation suggests that mice deficient in Oatp2b1 provide a valuable tool to study the in vivo importance of this transporter. In addition, our studies have identified novel potent inhibitors of OATP2B1 among the class of tyrosine kinase inhibitors, a rapidly expanding class of drugs used in various therapeutic areas that may cause drug-drug interactions with OATP2B1 substrates. |
doi_str_mv | 10.1124/dmd.119.090316 |
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The current investigation suggests that mice deficient in Oatp2b1 provide a valuable tool to study the in vivo importance of this transporter. In addition, our studies have identified novel potent inhibitors of OATP2B1 among the class of tyrosine kinase inhibitors, a rapidly expanding class of drugs used in various therapeutic areas that may cause drug-drug interactions with OATP2B1 substrates.</description><identifier>ISSN: 0090-9556</identifier><identifier>EISSN: 1521-009X</identifier><identifier>DOI: 10.1124/dmd.119.090316</identifier><identifier>PMID: 32114507</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Administration, Oral ; Animals ; Drug Interactions ; Female ; Fluvastatin - administration & dosage ; Fluvastatin - pharmacokinetics ; HEK293 Cells ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics ; Intestinal Absorption ; Intestinal Mucosa - metabolism ; Male ; Mice ; Mice, Knockout ; Organic Anion Transporters - genetics ; Organic Anion Transporters - metabolism ; RNA - genetics ; RNA - metabolism</subject><ispartof>Drug metabolism and disposition, 2020-05, Vol.48 (5), p.419-425</ispartof><rights>2020 American Society for Pharmacology and Experimental Therapeutics</rights><rights>Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.</rights><rights>Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c505t-9b4e0c9cbdd0641238f4e3b678134fc2adb72abfdbc291292526ccc5cd03f4c3</citedby><cites>FETCH-LOGICAL-c505t-9b4e0c9cbdd0641238f4e3b678134fc2adb72abfdbc291292526ccc5cd03f4c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32114507$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Mingqing</creatorcontrib><creatorcontrib>Hu, Shuiying</creatorcontrib><creatorcontrib>Li, Yang</creatorcontrib><creatorcontrib>Gibson, Alice A.</creatorcontrib><creatorcontrib>Fu, Qiang</creatorcontrib><creatorcontrib>Baker, Sharyn D.</creatorcontrib><creatorcontrib>Sparreboom, Alex</creatorcontrib><title>Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions</title><title>Drug metabolism and disposition</title><addtitle>Drug Metab Dispos</addtitle><description>The organic anion transporting polypeptide (OATP)2B1 is localized on the basolateral membrane of hepatocytes and is expressed in enterocytes. Based on its distribution pattern and functional similarity to OATP1B-type transporters, OATP2B1 might have a role in the absorption and disposition of a range of xenobiotics. Although several prescription drugs, including hydroxymethylglutaryl-coenzyme A-CoA reductase inhibitors (statins) such as fluvastatin, are OATP2B1 substrates in vitro, evidence supporting the in vivo relevance of this transporter remains limited, and most has relied on substrate-inhibitor interactions resulting in altered pharmacokinetic properties of the victim drugs. To address this knowledge deficit, we developed and characterized an Oatp2b1-deficient mouse model and evaluated the impact of this transporter on the absorption and disposition of fluvastatin. Consistent with the intestinal localization of Oatp2b1, we found that the genetic deletion or pharmacological inhibition of Oatp2b1 was associated with decreased absorption of fluvastatin by 2- to 3-fold. The availability of a viable Oatp2b1-deficient mouse model provides an opportunity to unequivocally determine the contribution of this transporter to the absorption and drug-drug interaction potential of drugs.
The current investigation suggests that mice deficient in Oatp2b1 provide a valuable tool to study the in vivo importance of this transporter. In addition, our studies have identified novel potent inhibitors of OATP2B1 among the class of tyrosine kinase inhibitors, a rapidly expanding class of drugs used in various therapeutic areas that may cause drug-drug interactions with OATP2B1 substrates.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Drug Interactions</subject><subject>Female</subject><subject>Fluvastatin - administration & dosage</subject><subject>Fluvastatin - pharmacokinetics</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics</subject><subject>Intestinal Absorption</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Organic Anion Transporters - genetics</subject><subject>Organic Anion Transporters - metabolism</subject><subject>RNA - genetics</subject><subject>RNA - metabolism</subject><issn>0090-9556</issn><issn>1521-009X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1UMtKAzEUDaLYWt26lPmBqXnOTBYKpb4KhYJ04S7kNTXSToZkWvDvTTtadOHqHu55XO4B4BrBMUKY3pqNSYCPIYcEFSdgiBhGOYT87RQM04A5Z6wYgIsYPyBElBJ-DgYEI0QZLIfg7tWvbebrbCG7FiuUuSZ7CNtVNlHRh7ZzvslkYw67_EDMms4GqfdMvARntVxHe_U9R2D59LicvuTzxfNsOpnnmkHW5VxRCzXXyhhYUIRJVVNLVFFWiNBaY2lUiaWqjdKYI8wxw4XWmmkDSU01GYH7Prbdqo012jZdkGvRBreR4VN46cRfpnHvYuV3okQVhLRKAeM-QAcfY7D10Yug2PcoUo8JcNH3mAw3vy8e5T_FJUHVC2x6e-dsEFE722hrXLC6E8a7_7K_AGQlghA</recordid><startdate>20200501</startdate><enddate>20200501</enddate><creator>Chen, Mingqing</creator><creator>Hu, Shuiying</creator><creator>Li, Yang</creator><creator>Gibson, Alice A.</creator><creator>Fu, Qiang</creator><creator>Baker, Sharyn D.</creator><creator>Sparreboom, Alex</creator><general>Elsevier Inc</general><general>The American Society for Pharmacology and Experimental Therapeutics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20200501</creationdate><title>Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions</title><author>Chen, Mingqing ; Hu, Shuiying ; Li, Yang ; Gibson, Alice A. ; Fu, Qiang ; Baker, Sharyn D. ; Sparreboom, Alex</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c505t-9b4e0c9cbdd0641238f4e3b678134fc2adb72abfdbc291292526ccc5cd03f4c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Drug Interactions</topic><topic>Female</topic><topic>Fluvastatin - administration & dosage</topic><topic>Fluvastatin - pharmacokinetics</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics</topic><topic>Intestinal Absorption</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Organic Anion Transporters - genetics</topic><topic>Organic Anion Transporters - metabolism</topic><topic>RNA - genetics</topic><topic>RNA - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Mingqing</creatorcontrib><creatorcontrib>Hu, Shuiying</creatorcontrib><creatorcontrib>Li, Yang</creatorcontrib><creatorcontrib>Gibson, Alice A.</creatorcontrib><creatorcontrib>Fu, Qiang</creatorcontrib><creatorcontrib>Baker, Sharyn D.</creatorcontrib><creatorcontrib>Sparreboom, Alex</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Drug metabolism and disposition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Mingqing</au><au>Hu, Shuiying</au><au>Li, Yang</au><au>Gibson, Alice A.</au><au>Fu, Qiang</au><au>Baker, Sharyn D.</au><au>Sparreboom, Alex</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions</atitle><jtitle>Drug metabolism and disposition</jtitle><addtitle>Drug Metab Dispos</addtitle><date>2020-05-01</date><risdate>2020</risdate><volume>48</volume><issue>5</issue><spage>419</spage><epage>425</epage><pages>419-425</pages><issn>0090-9556</issn><eissn>1521-009X</eissn><abstract>The organic anion transporting polypeptide (OATP)2B1 is localized on the basolateral membrane of hepatocytes and is expressed in enterocytes. Based on its distribution pattern and functional similarity to OATP1B-type transporters, OATP2B1 might have a role in the absorption and disposition of a range of xenobiotics. Although several prescription drugs, including hydroxymethylglutaryl-coenzyme A-CoA reductase inhibitors (statins) such as fluvastatin, are OATP2B1 substrates in vitro, evidence supporting the in vivo relevance of this transporter remains limited, and most has relied on substrate-inhibitor interactions resulting in altered pharmacokinetic properties of the victim drugs. To address this knowledge deficit, we developed and characterized an Oatp2b1-deficient mouse model and evaluated the impact of this transporter on the absorption and disposition of fluvastatin. Consistent with the intestinal localization of Oatp2b1, we found that the genetic deletion or pharmacological inhibition of Oatp2b1 was associated with decreased absorption of fluvastatin by 2- to 3-fold. The availability of a viable Oatp2b1-deficient mouse model provides an opportunity to unequivocally determine the contribution of this transporter to the absorption and drug-drug interaction potential of drugs.
The current investigation suggests that mice deficient in Oatp2b1 provide a valuable tool to study the in vivo importance of this transporter. In addition, our studies have identified novel potent inhibitors of OATP2B1 among the class of tyrosine kinase inhibitors, a rapidly expanding class of drugs used in various therapeutic areas that may cause drug-drug interactions with OATP2B1 substrates.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32114507</pmid><doi>10.1124/dmd.119.090316</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Administration, Oral Animals Drug Interactions Female Fluvastatin - administration & dosage Fluvastatin - pharmacokinetics HEK293 Cells Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics Intestinal Absorption Intestinal Mucosa - metabolism Male Mice Mice, Knockout Organic Anion Transporters - genetics Organic Anion Transporters - metabolism RNA - genetics RNA - metabolism |
title | Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions |
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