PBPK modeling of irbesartan: incorporation of hepatic uptake
Physiological based pharmacokinetic (PBPK) modeling is now commonly used in drug development to integrate human or animal physiological data in order to predict pharmacokinetic profiles. The aim of this work was to construct and refine a PBPK model of irbesartan taking into account its active uptake...
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| Veröffentlicht in: | Biopharmaceutics & drug disposition 2015-11, Vol.36 (8), p.491-506 |
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| creator | Chapy, Helene Klieber, Sylvie Brun, Priscilla Gerbal-Chaloin, Sabine Boulenc, Xavier Nicolas, Olivier |
| description | Physiological based pharmacokinetic (PBPK) modeling is now commonly used in drug development to integrate human or animal physiological data in order to predict pharmacokinetic profiles. The aim of this work was to construct and refine a PBPK model of irbesartan taking into account its active uptake via OATP1B1/B3 in order to predict more accurately its pharmacokinetic profile using Simcyp®. The activity and expression of the human hepatocyte transporters OATP1B1 and OATP1B3 were studied. The relative activity factors (RAFs) for OATP1B1 and OATP1B3 transporters were calculated from intrinsic clearances obtained by concentration dependent uptake experiments in human hepatocytes and HEK overexpressing cells: RAF1B1 using estrone‐3‐sulfate and pitavastatine clearances, and RAF1B3 using cholecystokinine octapeptide (CCK‐8) clearances. The relative expression factor (REF) was calculated by comparing immunoblotting of hepatocytes (REFHH) or tissues (REFtissue) with those of overexpressing HEK cells for each transporter. These scaling factors were applied in a PBPK model of irbesartan using the Simcyp® simulator. Pharmacokinetic simulation using REFHH (1.82 for OATP1B1, 8.03 for OATP1B3) as an extrapolation factor was the closest to the human clinical pharmacokinetic profile of irbesartan. These investigations show the importance of integrating the contribution of the active uptake of a drug in the liver to improve PBPK modeling. Copyright © 2015 John Wiley & Sons, Ltd. |
| doi_str_mv | 10.1002/bdd.1961 |
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The aim of this work was to construct and refine a PBPK model of irbesartan taking into account its active uptake via OATP1B1/B3 in order to predict more accurately its pharmacokinetic profile using Simcyp®. The activity and expression of the human hepatocyte transporters OATP1B1 and OATP1B3 were studied. The relative activity factors (RAFs) for OATP1B1 and OATP1B3 transporters were calculated from intrinsic clearances obtained by concentration dependent uptake experiments in human hepatocytes and HEK overexpressing cells: RAF1B1 using estrone‐3‐sulfate and pitavastatine clearances, and RAF1B3 using cholecystokinine octapeptide (CCK‐8) clearances. The relative expression factor (REF) was calculated by comparing immunoblotting of hepatocytes (REFHH) or tissues (REFtissue) with those of overexpressing HEK cells for each transporter. These scaling factors were applied in a PBPK model of irbesartan using the Simcyp® simulator. Pharmacokinetic simulation using REFHH (1.82 for OATP1B1, 8.03 for OATP1B3) as an extrapolation factor was the closest to the human clinical pharmacokinetic profile of irbesartan. These investigations show the importance of integrating the contribution of the active uptake of a drug in the liver to improve PBPK modeling. Copyright © 2015 John Wiley & Sons, Ltd.</description><identifier>ISSN: 0142-2782</identifier><identifier>EISSN: 1099-081X</identifier><identifier>DOI: 10.1002/bdd.1961</identifier><identifier>PMID: 26037524</identifier><identifier>CODEN: BDDID8</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Adult ; Angiotensin II Type 1 Receptor Blockers - pharmacokinetics ; Biphenyl Compounds - pharmacokinetics ; Blotting, Western ; Cells, Cultured ; Chromatography, Liquid ; Computer Simulation ; Glycosylation ; HEK293 Cells ; Hepatocytes - metabolism ; Humans ; irbesartan ; Kinetics ; Life Sciences ; Liver - metabolism ; Models, Biological ; OATP ; Organic Anion Transporters - genetics ; Organic Anion Transporters - metabolism ; Organic Anion Transporters, Sodium-Independent - genetics ; Organic Anion Transporters, Sodium-Independent - metabolism ; PBPK ; Primary Cell Culture ; scaling factor ; Solute Carrier Organic Anion Transporter Family Member 1b1 ; Solute Carrier Organic Anion Transporter Family Member 1B3 ; Tandem Mass Spectrometry ; Tetrazoles - pharmacokinetics ; Transfection ; transporter</subject><ispartof>Biopharmaceutics & drug disposition, 2015-11, Vol.36 (8), p.491-506</ispartof><rights>Copyright © 2015 John Wiley & Sons, Ltd.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4911-76d86174c52acbe704733524a84d2ec6f3f01365e8358cc07278fc6b186d49d83</citedby><cites>FETCH-LOGICAL-c4911-76d86174c52acbe704733524a84d2ec6f3f01365e8358cc07278fc6b186d49d83</cites><orcidid>0000-0002-2549-7899</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.1961$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fbdd.1961$$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/26037524$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.umontpellier.fr/hal-01838123$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Chapy, Helene</creatorcontrib><creatorcontrib>Klieber, Sylvie</creatorcontrib><creatorcontrib>Brun, Priscilla</creatorcontrib><creatorcontrib>Gerbal-Chaloin, Sabine</creatorcontrib><creatorcontrib>Boulenc, Xavier</creatorcontrib><creatorcontrib>Nicolas, Olivier</creatorcontrib><title>PBPK modeling of irbesartan: incorporation of hepatic uptake</title><title>Biopharmaceutics & drug disposition</title><addtitle>Biopharm. Drug Dispos</addtitle><description>Physiological based pharmacokinetic (PBPK) modeling is now commonly used in drug development to integrate human or animal physiological data in order to predict pharmacokinetic profiles. The aim of this work was to construct and refine a PBPK model of irbesartan taking into account its active uptake via OATP1B1/B3 in order to predict more accurately its pharmacokinetic profile using Simcyp®. The activity and expression of the human hepatocyte transporters OATP1B1 and OATP1B3 were studied. The relative activity factors (RAFs) for OATP1B1 and OATP1B3 transporters were calculated from intrinsic clearances obtained by concentration dependent uptake experiments in human hepatocytes and HEK overexpressing cells: RAF1B1 using estrone‐3‐sulfate and pitavastatine clearances, and RAF1B3 using cholecystokinine octapeptide (CCK‐8) clearances. The relative expression factor (REF) was calculated by comparing immunoblotting of hepatocytes (REFHH) or tissues (REFtissue) with those of overexpressing HEK cells for each transporter. These scaling factors were applied in a PBPK model of irbesartan using the Simcyp® simulator. Pharmacokinetic simulation using REFHH (1.82 for OATP1B1, 8.03 for OATP1B3) as an extrapolation factor was the closest to the human clinical pharmacokinetic profile of irbesartan. These investigations show the importance of integrating the contribution of the active uptake of a drug in the liver to improve PBPK modeling. Copyright © 2015 John Wiley & Sons, Ltd.</description><subject>Adult</subject><subject>Angiotensin II Type 1 Receptor Blockers - pharmacokinetics</subject><subject>Biphenyl Compounds - pharmacokinetics</subject><subject>Blotting, Western</subject><subject>Cells, Cultured</subject><subject>Chromatography, Liquid</subject><subject>Computer Simulation</subject><subject>Glycosylation</subject><subject>HEK293 Cells</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>irbesartan</subject><subject>Kinetics</subject><subject>Life Sciences</subject><subject>Liver - metabolism</subject><subject>Models, Biological</subject><subject>OATP</subject><subject>Organic Anion Transporters - genetics</subject><subject>Organic Anion Transporters - metabolism</subject><subject>Organic Anion Transporters, Sodium-Independent - genetics</subject><subject>Organic Anion Transporters, Sodium-Independent - metabolism</subject><subject>PBPK</subject><subject>Primary Cell Culture</subject><subject>scaling factor</subject><subject>Solute Carrier Organic Anion Transporter Family Member 1b1</subject><subject>Solute Carrier Organic Anion Transporter Family Member 1B3</subject><subject>Tandem Mass Spectrometry</subject><subject>Tetrazoles - pharmacokinetics</subject><subject>Transfection</subject><subject>transporter</subject><issn>0142-2782</issn><issn>1099-081X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kN1uFCEYQElj025rE5_ATOKNvZjKBwwwxpu2q13j2p9UrXeEYRhLOzuMMKP27ctm1zUx6RUETg4fB6EXgI8AY_KmqusjKDlsoQngssyxhO_P0AQDIzkRkuyivRjvMMYcAHbQLuGYioKwCXp3eXL5KVv42rau-5H5JnOhslGHQXdvM9cZH3of9OB8t7y8tX3am2zsB31vn6PtRrfRHqzXffT1w_svp7N8fnH28fR4nhtWAuSC15KDYKYg2lRWYCYoTa9ryWpiDW9og4HywkpaSGOwSCM3hlcgec3KWtJ9dLjy3upW9cEtdHhQXjs1O56r5RkGSSUQ-gsS-3rF9sH_HG0c1MJFY9tWd9aPUYHgWJYMSprQV_-hd34MXfpJogoBqSKT_4Qm-BiDbTYTAFbL-irVV8v6CX25Fo7VwtYb8G_uBOQr4Ldr7cOTInUyna6Fa97Fwf7Z8DrcKy6SUt2cn6mr2c23zzAt1DV9BF3umOY</recordid><startdate>201511</startdate><enddate>201511</enddate><creator>Chapy, Helene</creator><creator>Klieber, Sylvie</creator><creator>Brun, Priscilla</creator><creator>Gerbal-Chaloin, Sabine</creator><creator>Boulenc, Xavier</creator><creator>Nicolas, Olivier</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><general>Wiley</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>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><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-2549-7899</orcidid></search><sort><creationdate>201511</creationdate><title>PBPK modeling of irbesartan: incorporation of hepatic uptake</title><author>Chapy, Helene ; Klieber, Sylvie ; Brun, Priscilla ; Gerbal-Chaloin, Sabine ; Boulenc, Xavier ; Nicolas, Olivier</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4911-76d86174c52acbe704733524a84d2ec6f3f01365e8358cc07278fc6b186d49d83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Angiotensin II Type 1 Receptor Blockers - pharmacokinetics</topic><topic>Biphenyl Compounds - pharmacokinetics</topic><topic>Blotting, Western</topic><topic>Cells, Cultured</topic><topic>Chromatography, Liquid</topic><topic>Computer Simulation</topic><topic>Glycosylation</topic><topic>HEK293 Cells</topic><topic>Hepatocytes - metabolism</topic><topic>Humans</topic><topic>irbesartan</topic><topic>Kinetics</topic><topic>Life Sciences</topic><topic>Liver - metabolism</topic><topic>Models, Biological</topic><topic>OATP</topic><topic>Organic Anion Transporters - genetics</topic><topic>Organic Anion Transporters - metabolism</topic><topic>Organic Anion Transporters, Sodium-Independent - genetics</topic><topic>Organic Anion Transporters, Sodium-Independent - metabolism</topic><topic>PBPK</topic><topic>Primary Cell Culture</topic><topic>scaling factor</topic><topic>Solute Carrier Organic Anion Transporter Family Member 1b1</topic><topic>Solute Carrier Organic Anion Transporter Family Member 1B3</topic><topic>Tandem Mass Spectrometry</topic><topic>Tetrazoles - pharmacokinetics</topic><topic>Transfection</topic><topic>transporter</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chapy, Helene</creatorcontrib><creatorcontrib>Klieber, Sylvie</creatorcontrib><creatorcontrib>Brun, Priscilla</creatorcontrib><creatorcontrib>Gerbal-Chaloin, Sabine</creatorcontrib><creatorcontrib>Boulenc, Xavier</creatorcontrib><creatorcontrib>Nicolas, Olivier</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>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><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Biopharmaceutics & drug disposition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chapy, Helene</au><au>Klieber, Sylvie</au><au>Brun, Priscilla</au><au>Gerbal-Chaloin, Sabine</au><au>Boulenc, Xavier</au><au>Nicolas, Olivier</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PBPK modeling of irbesartan: incorporation of hepatic uptake</atitle><jtitle>Biopharmaceutics & drug disposition</jtitle><addtitle>Biopharm. Drug Dispos</addtitle><date>2015-11</date><risdate>2015</risdate><volume>36</volume><issue>8</issue><spage>491</spage><epage>506</epage><pages>491-506</pages><issn>0142-2782</issn><eissn>1099-081X</eissn><coden>BDDID8</coden><abstract>Physiological based pharmacokinetic (PBPK) modeling is now commonly used in drug development to integrate human or animal physiological data in order to predict pharmacokinetic profiles. The aim of this work was to construct and refine a PBPK model of irbesartan taking into account its active uptake via OATP1B1/B3 in order to predict more accurately its pharmacokinetic profile using Simcyp®. The activity and expression of the human hepatocyte transporters OATP1B1 and OATP1B3 were studied. The relative activity factors (RAFs) for OATP1B1 and OATP1B3 transporters were calculated from intrinsic clearances obtained by concentration dependent uptake experiments in human hepatocytes and HEK overexpressing cells: RAF1B1 using estrone‐3‐sulfate and pitavastatine clearances, and RAF1B3 using cholecystokinine octapeptide (CCK‐8) clearances. The relative expression factor (REF) was calculated by comparing immunoblotting of hepatocytes (REFHH) or tissues (REFtissue) with those of overexpressing HEK cells for each transporter. These scaling factors were applied in a PBPK model of irbesartan using the Simcyp® simulator. Pharmacokinetic simulation using REFHH (1.82 for OATP1B1, 8.03 for OATP1B3) as an extrapolation factor was the closest to the human clinical pharmacokinetic profile of irbesartan. These investigations show the importance of integrating the contribution of the active uptake of a drug in the liver to improve PBPK modeling. Copyright © 2015 John Wiley & Sons, Ltd.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>26037524</pmid><doi>10.1002/bdd.1961</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-2549-7899</orcidid></addata></record> |
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| source | Wiley Online Library - AutoHoldings Journals; MEDLINE |
| subjects | Adult Angiotensin II Type 1 Receptor Blockers - pharmacokinetics Biphenyl Compounds - pharmacokinetics Blotting, Western Cells, Cultured Chromatography, Liquid Computer Simulation Glycosylation HEK293 Cells Hepatocytes - metabolism Humans irbesartan Kinetics Life Sciences Liver - metabolism Models, Biological OATP Organic Anion Transporters - genetics Organic Anion Transporters - metabolism Organic Anion Transporters, Sodium-Independent - genetics Organic Anion Transporters, Sodium-Independent - metabolism PBPK Primary Cell Culture scaling factor Solute Carrier Organic Anion Transporter Family Member 1b1 Solute Carrier Organic Anion Transporter Family Member 1B3 Tandem Mass Spectrometry Tetrazoles - pharmacokinetics Transfection transporter |
| title | PBPK modeling of irbesartan: incorporation of hepatic uptake |
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