Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1
Transporter‐mediated drug‐drug interactions (DDIs) are a major cause of drug toxicities. Using published genome‐wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10−8). Of these, 12...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 2016-11, Vol.100 (5), p.524-536 |
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| creator | Yee, SW Giacomini, MM Hsueh, C-H Weitz, D Liang, X Goswami, S Kinchen, JM Coelho, A Zur, AA Mertsch, K Brian, W Kroetz, DL Giacomini, KM |
| description | Transporter‐mediated drug‐drug interactions (DDIs) are a major cause of drug toxicities. Using published genome‐wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10−8). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine (CSA) vs. placebo (q‐value < 0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter‐mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established. |
| doi_str_mv | 10.1002/cpt.434 |
| format | Article |
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Using published genome‐wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10−8). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine (CSA) vs. placebo (q‐value < 0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter‐mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established.</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1002/cpt.434</identifier><identifier>PMID: 27447836</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>Bile Acids and Salts - blood ; Biomarkers - metabolism ; Cyclosporine - pharmacology ; Dicarboxylic Acids - blood ; Drug Interactions - genetics ; Fatty Acids - blood ; Genome-Wide Association Study ; HEK293 Cells ; Humans ; Liver-Specific Organic Anion Transporter 1 - antagonists & inhibitors ; Liver-Specific Organic Anion Transporter 1 - genetics ; Liver-Specific Organic Anion Transporter 1 - metabolism ; Metabolomics ; Myristates - metabolism ; Organic Anion Transport Protein 1 - metabolism ; Organic Anion Transporters, Sodium-Independent - metabolism ; Palmitic Acids - metabolism ; Pravastatin - pharmacology</subject><ispartof>Clinical pharmacology and therapeutics, 2016-11, Vol.100 (5), p.524-536</ispartof><rights>2016 American Society for Clinical Pharmacology and Therapeutics</rights><rights>2016 American Society for Clinical Pharmacology and Therapeutics.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6494-9595d3528bcb99650f7264567919f67ba4adf5174360dfa8947f6df580a644a33</citedby><cites>FETCH-LOGICAL-c6494-9595d3528bcb99650f7264567919f67ba4adf5174360dfa8947f6df580a644a33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcpt.434$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcpt.434$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27447836$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yee, SW</creatorcontrib><creatorcontrib>Giacomini, MM</creatorcontrib><creatorcontrib>Hsueh, C-H</creatorcontrib><creatorcontrib>Weitz, D</creatorcontrib><creatorcontrib>Liang, X</creatorcontrib><creatorcontrib>Goswami, S</creatorcontrib><creatorcontrib>Kinchen, JM</creatorcontrib><creatorcontrib>Coelho, A</creatorcontrib><creatorcontrib>Zur, AA</creatorcontrib><creatorcontrib>Mertsch, K</creatorcontrib><creatorcontrib>Brian, W</creatorcontrib><creatorcontrib>Kroetz, DL</creatorcontrib><creatorcontrib>Giacomini, KM</creatorcontrib><title>Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin. Pharmacol. Ther</addtitle><description>Transporter‐mediated drug‐drug interactions (DDIs) are a major cause of drug toxicities. Using published genome‐wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10−8). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine (CSA) vs. placebo (q‐value < 0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter‐mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established.</description><subject>Bile Acids and Salts - blood</subject><subject>Biomarkers - metabolism</subject><subject>Cyclosporine - pharmacology</subject><subject>Dicarboxylic Acids - blood</subject><subject>Drug Interactions - genetics</subject><subject>Fatty Acids - blood</subject><subject>Genome-Wide Association Study</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Liver-Specific Organic Anion Transporter 1 - antagonists & inhibitors</subject><subject>Liver-Specific Organic Anion Transporter 1 - genetics</subject><subject>Liver-Specific Organic Anion Transporter 1 - metabolism</subject><subject>Metabolomics</subject><subject>Myristates - metabolism</subject><subject>Organic Anion Transport Protein 1 - metabolism</subject><subject>Organic Anion Transporters, Sodium-Independent - metabolism</subject><subject>Palmitic Acids - metabolism</subject><subject>Pravastatin - pharmacology</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMtOwzAQRS0EgvIQf4C8Y4ECdvyKN0ht1RYQlAqKYGc5iQOGJK7ilMffYxSoYMHKY8-Z69EBYB-jY4xQfJIt2mNK6BroYUbiiDPC1kEPISQjGRO-Bba9fw5XKpNkE2zFglKREN4D6ZVpdepKV9kM6jqHE1O7ykRvNjew773LrG6tq-Ftu8yt8fDGvBpdwplrTd3aUI3q3D2GoaWHA-sq3byYxsPCNfC6P5_hAd4FG4Uuvdn7PnfA3Xg0H55Fl9eT82H_Mso4lTSSTLKcsDhJs1RKzlAhYk4ZFxLLgotUU50XDAtKOMoLnUgqCh5eEqQ5pZqQHXDa5S6WaWXyLOzX6FItGhuW-lBOW_W3U9sn9eheFSecYcRDwGEXkDXO-8YUq1mM1JdmFTSroDmQB7-_WnE_XgNw1AFvtjQf_-Wo4WzexUUdbX1r3ld0UKm4IIKp--lETR_G8-nFJFGYfAJFT5Y-</recordid><startdate>201611</startdate><enddate>201611</enddate><creator>Yee, SW</creator><creator>Giacomini, MM</creator><creator>Hsueh, C-H</creator><creator>Weitz, D</creator><creator>Liang, X</creator><creator>Goswami, S</creator><creator>Kinchen, JM</creator><creator>Coelho, A</creator><creator>Zur, AA</creator><creator>Mertsch, K</creator><creator>Brian, W</creator><creator>Kroetz, DL</creator><creator>Giacomini, KM</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</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><scope>5PM</scope></search><sort><creationdate>201611</creationdate><title>Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1</title><author>Yee, SW ; Giacomini, MM ; Hsueh, C-H ; Weitz, D ; Liang, X ; Goswami, S ; Kinchen, JM ; Coelho, A ; Zur, AA ; Mertsch, K ; Brian, W ; Kroetz, DL ; Giacomini, KM</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6494-9595d3528bcb99650f7264567919f67ba4adf5174360dfa8947f6df580a644a33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Bile Acids and Salts - blood</topic><topic>Biomarkers - metabolism</topic><topic>Cyclosporine - pharmacology</topic><topic>Dicarboxylic Acids - blood</topic><topic>Drug Interactions - genetics</topic><topic>Fatty Acids - blood</topic><topic>Genome-Wide Association Study</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Liver-Specific Organic Anion Transporter 1 - antagonists & inhibitors</topic><topic>Liver-Specific Organic Anion Transporter 1 - genetics</topic><topic>Liver-Specific Organic Anion Transporter 1 - metabolism</topic><topic>Metabolomics</topic><topic>Myristates - metabolism</topic><topic>Organic Anion Transport Protein 1 - metabolism</topic><topic>Organic Anion Transporters, Sodium-Independent - metabolism</topic><topic>Palmitic Acids - metabolism</topic><topic>Pravastatin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yee, SW</creatorcontrib><creatorcontrib>Giacomini, MM</creatorcontrib><creatorcontrib>Hsueh, C-H</creatorcontrib><creatorcontrib>Weitz, D</creatorcontrib><creatorcontrib>Liang, X</creatorcontrib><creatorcontrib>Goswami, S</creatorcontrib><creatorcontrib>Kinchen, JM</creatorcontrib><creatorcontrib>Coelho, A</creatorcontrib><creatorcontrib>Zur, AA</creatorcontrib><creatorcontrib>Mertsch, K</creatorcontrib><creatorcontrib>Brian, W</creatorcontrib><creatorcontrib>Kroetz, DL</creatorcontrib><creatorcontrib>Giacomini, KM</creatorcontrib><collection>Istex</collection><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>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yee, SW</au><au>Giacomini, MM</au><au>Hsueh, C-H</au><au>Weitz, D</au><au>Liang, X</au><au>Goswami, S</au><au>Kinchen, JM</au><au>Coelho, A</au><au>Zur, AA</au><au>Mertsch, K</au><au>Brian, W</au><au>Kroetz, DL</au><au>Giacomini, KM</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin. Pharmacol. Ther</addtitle><date>2016-11</date><risdate>2016</risdate><volume>100</volume><issue>5</issue><spage>524</spage><epage>536</epage><pages>524-536</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><abstract>Transporter‐mediated drug‐drug interactions (DDIs) are a major cause of drug toxicities. Using published genome‐wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10−8). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine (CSA) vs. placebo (q‐value < 0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. 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| ispartof | Clinical pharmacology and therapeutics, 2016-11, Vol.100 (5), p.524-536 |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Bile Acids and Salts - blood Biomarkers - metabolism Cyclosporine - pharmacology Dicarboxylic Acids - blood Drug Interactions - genetics Fatty Acids - blood Genome-Wide Association Study HEK293 Cells Humans Liver-Specific Organic Anion Transporter 1 - antagonists & inhibitors Liver-Specific Organic Anion Transporter 1 - genetics Liver-Specific Organic Anion Transporter 1 - metabolism Metabolomics Myristates - metabolism Organic Anion Transport Protein 1 - metabolism Organic Anion Transporters, Sodium-Independent - metabolism Palmitic Acids - metabolism Pravastatin - pharmacology |
| title | Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1 |
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