Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline
The effects of OATP1B1, OAT3, and MRP2 on the pharmacokinetics of eluxadoline, an oral, locally active, opioid receptor agonist/antagonist being developed for treatment of IBS‐d were assessed in vivo. Coadministration of a single 200 mg dose of eluxadoline with cyclosporine, and probenecid increased...
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| Veröffentlicht in: | Journal of clinical pharmacology 2015-05, Vol.55 (5), p.534-542 |
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| creator | Davenport, J. Michael Covington, Paul Bonifacio, Laura McIntyre, Gail Venitz, Jürgen |
| description | The effects of OATP1B1, OAT3, and MRP2 on the pharmacokinetics of eluxadoline, an oral, locally active, opioid receptor agonist/antagonist being developed for treatment of IBS‐d were assessed in vivo. Coadministration of a single 200 mg dose of eluxadoline with cyclosporine, and probenecid increased eluxadoline systemic exposure [AUC(0–inf)] by 4.4‐ and 1.4‐fold, respectively, whereas peak exposure (Cmax) increased 6.2‐fold and 1.3‐fold, respectively. Cyclosporine had little effect on renal clearance (CLren) of eluxadoline whereas probenecid reduced CLren by nearly 50%. These study results suggested that sinusoidal OATP1B1‐mediated hepatic uptake of eluxadoline (during first‐pass and systemic extraction) plays a major role in its absorption and disposition, whereas OAT3‐mediated basolateral uptake in the proximal renal tubules and MRP2‐mediated canalicular and renal tubular apical efflux play only minor roles in its overall disposition. All treatments were safe and well tolerated. |
| doi_str_mv | 10.1002/jcph.442 |
| format | Article |
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Michael ; Covington, Paul ; Bonifacio, Laura ; McIntyre, Gail ; Venitz, Jürgen</creator><creatorcontrib>Davenport, J. Michael ; Covington, Paul ; Bonifacio, Laura ; McIntyre, Gail ; Venitz, Jürgen</creatorcontrib><description>The effects of OATP1B1, OAT3, and MRP2 on the pharmacokinetics of eluxadoline, an oral, locally active, opioid receptor agonist/antagonist being developed for treatment of IBS‐d were assessed in vivo. Coadministration of a single 200 mg dose of eluxadoline with cyclosporine, and probenecid increased eluxadoline systemic exposure [AUC(0–inf)] by 4.4‐ and 1.4‐fold, respectively, whereas peak exposure (Cmax) increased 6.2‐fold and 1.3‐fold, respectively. Cyclosporine had little effect on renal clearance (CLren) of eluxadoline whereas probenecid reduced CLren by nearly 50%. These study results suggested that sinusoidal OATP1B1‐mediated hepatic uptake of eluxadoline (during first‐pass and systemic extraction) plays a major role in its absorption and disposition, whereas OAT3‐mediated basolateral uptake in the proximal renal tubules and MRP2‐mediated canalicular and renal tubular apical efflux play only minor roles in its overall disposition. All treatments were safe and well tolerated.</description><identifier>ISSN: 0091-2700</identifier><identifier>EISSN: 1552-4604</identifier><identifier>DOI: 10.1002/jcph.442</identifier><identifier>PMID: 25491493</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Adult ; Area Under Curve ; Cross-Over Studies ; cyclosporine ; Cyclosporine - pharmacology ; drug interaction ; eluxadoline ; Half-Life ; Humans ; Imidazoles - administration & dosage ; Imidazoles - adverse effects ; Imidazoles - pharmacokinetics ; Metabolic Clearance Rate ; Middle Aged ; Multidrug Resistance-Associated Proteins - metabolism ; Organic Anion Transporters - metabolism ; Organic Anion Transporters, Sodium-Independent - metabolism ; Pharmacogenomics ; pharmacokinetics ; Phenylalanine - administration & dosage ; Phenylalanine - adverse effects ; Phenylalanine - analogs & derivatives ; Phenylalanine - pharmacokinetics ; probenecid ; Probenecid - pharmacology ; Solute Carrier Organic Anion Transporter Family Member 1b1</subject><ispartof>Journal of clinical pharmacology, 2015-05, Vol.55 (5), p.534-542</ispartof><rights>2015 The Authors. Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology</rights><rights>2015 American College of Clinical Pharmacology</rights><rights>2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.</rights><rights>2015, The American College of Clinical Pharmacology</rights><rights>2015 The Authors. 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Michael</creatorcontrib><creatorcontrib>Covington, Paul</creatorcontrib><creatorcontrib>Bonifacio, Laura</creatorcontrib><creatorcontrib>McIntyre, Gail</creatorcontrib><creatorcontrib>Venitz, Jürgen</creatorcontrib><title>Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline</title><title>Journal of clinical pharmacology</title><addtitle>The Journal of Clinical Pharmacology</addtitle><description>The effects of OATP1B1, OAT3, and MRP2 on the pharmacokinetics of eluxadoline, an oral, locally active, opioid receptor agonist/antagonist being developed for treatment of IBS‐d were assessed in vivo. Coadministration of a single 200 mg dose of eluxadoline with cyclosporine, and probenecid increased eluxadoline systemic exposure [AUC(0–inf)] by 4.4‐ and 1.4‐fold, respectively, whereas peak exposure (Cmax) increased 6.2‐fold and 1.3‐fold, respectively. Cyclosporine had little effect on renal clearance (CLren) of eluxadoline whereas probenecid reduced CLren by nearly 50%. These study results suggested that sinusoidal OATP1B1‐mediated hepatic uptake of eluxadoline (during first‐pass and systemic extraction) plays a major role in its absorption and disposition, whereas OAT3‐mediated basolateral uptake in the proximal renal tubules and MRP2‐mediated canalicular and renal tubular apical efflux play only minor roles in its overall disposition. All treatments were safe and well tolerated.</description><subject>Adult</subject><subject>Area Under Curve</subject><subject>Cross-Over Studies</subject><subject>cyclosporine</subject><subject>Cyclosporine - pharmacology</subject><subject>drug interaction</subject><subject>eluxadoline</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Imidazoles - administration & dosage</subject><subject>Imidazoles - adverse effects</subject><subject>Imidazoles - pharmacokinetics</subject><subject>Metabolic Clearance Rate</subject><subject>Middle Aged</subject><subject>Multidrug Resistance-Associated Proteins - metabolism</subject><subject>Organic Anion Transporters - metabolism</subject><subject>Organic Anion Transporters, Sodium-Independent - metabolism</subject><subject>Pharmacogenomics</subject><subject>pharmacokinetics</subject><subject>Phenylalanine - administration & dosage</subject><subject>Phenylalanine - adverse effects</subject><subject>Phenylalanine - analogs & derivatives</subject><subject>Phenylalanine - pharmacokinetics</subject><subject>probenecid</subject><subject>Probenecid - pharmacology</subject><subject>Solute Carrier Organic Anion Transporter Family Member 1b1</subject><issn>0091-2700</issn><issn>1552-4604</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp1kU1v1DAQhiMEoktB4hegSFy4pMw4dj4uSGVVtkChCxRxtFxnTLKbjVM7oe2_x2GXpSDhi-3xM-_M-I2ipwhHCMBernRfH3HO7kUzFIIlPAN-P5oBlJiwHOAgeuT9CgAzLvBhdMAEL5GX6Sy6OjGG9BBbE4_9oNYUD051vrduIOfj8-OLNFZdNR2W-Bp_ncmYdry5C8YfPi9ZbLt4qCnua-U2Stt109HQaD9pU0hQlW1D6HH0wKjW05Pdfhh9fXNyMT9Nzs4Xb-fHZ4kWJRYJlQZFZhSgLiqRKqa4yQtigkGVVaiZKiuTXVZaCAyk0QXpokg1Uiog8Olh9Gqr24-XG6o0daHhVvau2Sh3K61q5N8vXVPL7_aH5BwYsCIIvNgJOHs1kh_kpvGa2lZ1ZEcvMcuRoUgxDejzf9CVHV0XxpOY50JAmQH8EdTOeu_I7JtBkJOPcvIx1GcBfXa3-T3427gA8C1wbdvJqXU7XpOTNal2qCWExYPvCQMMvxFuyRSaZkp2aU1Lt_-tL9_Nl6fbPnZ84we62fPKrWWWp7mQ3z4u5GJRfnmPy09ynv4ENC7GlA</recordid><startdate>201505</startdate><enddate>201505</enddate><creator>Davenport, J. Michael</creator><creator>Covington, Paul</creator><creator>Bonifacio, Laura</creator><creator>McIntyre, Gail</creator><creator>Venitz, Jürgen</creator><general>Blackwell Publishing Ltd</general><general>American College of Clinical Pharmacology</general><general>Wiley Subscription Services, Inc</general><general>BlackWell Publishing Ltd</general><scope>BSCLL</scope><scope>24P</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>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201505</creationdate><title>Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline</title><author>Davenport, J. Michael ; Covington, Paul ; Bonifacio, Laura ; McIntyre, Gail ; Venitz, Jürgen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5918-e9f156fa01c8d53a2a4f78e2520d6d1c2a9df6bdc551f15fc8ec883c1e35053a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Area Under Curve</topic><topic>Cross-Over Studies</topic><topic>cyclosporine</topic><topic>Cyclosporine - pharmacology</topic><topic>drug interaction</topic><topic>eluxadoline</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Imidazoles - administration & dosage</topic><topic>Imidazoles - adverse effects</topic><topic>Imidazoles - pharmacokinetics</topic><topic>Metabolic Clearance Rate</topic><topic>Middle Aged</topic><topic>Multidrug Resistance-Associated Proteins - metabolism</topic><topic>Organic Anion Transporters - metabolism</topic><topic>Organic Anion Transporters, Sodium-Independent - metabolism</topic><topic>Pharmacogenomics</topic><topic>pharmacokinetics</topic><topic>Phenylalanine - administration & dosage</topic><topic>Phenylalanine - adverse effects</topic><topic>Phenylalanine - analogs & derivatives</topic><topic>Phenylalanine - pharmacokinetics</topic><topic>probenecid</topic><topic>Probenecid - pharmacology</topic><topic>Solute Carrier Organic Anion Transporter Family Member 1b1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Davenport, J. Michael</creatorcontrib><creatorcontrib>Covington, Paul</creatorcontrib><creatorcontrib>Bonifacio, Laura</creatorcontrib><creatorcontrib>McIntyre, Gail</creatorcontrib><creatorcontrib>Venitz, Jürgen</creatorcontrib><collection>Istex</collection><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids 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>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Davenport, J. Michael</au><au>Covington, Paul</au><au>Bonifacio, Laura</au><au>McIntyre, Gail</au><au>Venitz, Jürgen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline</atitle><jtitle>Journal of clinical pharmacology</jtitle><addtitle>The Journal of Clinical Pharmacology</addtitle><date>2015-05</date><risdate>2015</risdate><volume>55</volume><issue>5</issue><spage>534</spage><epage>542</epage><pages>534-542</pages><issn>0091-2700</issn><eissn>1552-4604</eissn><abstract>The effects of OATP1B1, OAT3, and MRP2 on the pharmacokinetics of eluxadoline, an oral, locally active, opioid receptor agonist/antagonist being developed for treatment of IBS‐d were assessed in vivo. Coadministration of a single 200 mg dose of eluxadoline with cyclosporine, and probenecid increased eluxadoline systemic exposure [AUC(0–inf)] by 4.4‐ and 1.4‐fold, respectively, whereas peak exposure (Cmax) increased 6.2‐fold and 1.3‐fold, respectively. Cyclosporine had little effect on renal clearance (CLren) of eluxadoline whereas probenecid reduced CLren by nearly 50%. These study results suggested that sinusoidal OATP1B1‐mediated hepatic uptake of eluxadoline (during first‐pass and systemic extraction) plays a major role in its absorption and disposition, whereas OAT3‐mediated basolateral uptake in the proximal renal tubules and MRP2‐mediated canalicular and renal tubular apical efflux play only minor roles in its overall disposition. All treatments were safe and well tolerated.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>25491493</pmid><doi>10.1002/jcph.442</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Area Under Curve Cross-Over Studies cyclosporine Cyclosporine - pharmacology drug interaction eluxadoline Half-Life Humans Imidazoles - administration & dosage Imidazoles - adverse effects Imidazoles - pharmacokinetics Metabolic Clearance Rate Middle Aged Multidrug Resistance-Associated Proteins - metabolism Organic Anion Transporters - metabolism Organic Anion Transporters, Sodium-Independent - metabolism Pharmacogenomics pharmacokinetics Phenylalanine - administration & dosage Phenylalanine - adverse effects Phenylalanine - analogs & derivatives Phenylalanine - pharmacokinetics probenecid Probenecid - pharmacology Solute Carrier Organic Anion Transporter Family Member 1b1 |
| title | Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline |
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