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Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data
The aim of this study was to evaluate a strategy based on a physiologically based pharmacokinetic (PBPK) model for the prediction of PK profiles in human using in vitro data when elimination of compounds relies on active transport processes. The strategy was first applied to rat in vivo and in vitro...
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| Published in: | Journal of pharmacokinetics and pharmacodynamics 2009-12, Vol.36 (6), p.585-611 |
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| container_end_page | 611 |
| container_issue | 6 |
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| container_title | Journal of pharmacokinetics and pharmacodynamics |
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| creator | Poirier, Agnès Cascais, Anne-Christine Funk, Christoph Lavé, Thierry |
| description | The aim of this study was to evaluate a strategy based on a physiologically based pharmacokinetic (PBPK) model for the prediction of PK profiles in human using in vitro data when elimination of compounds relies on active transport processes. The strategy was first applied to rat in vivo and in vitro data in order to refine the PBPK model. The model could then be applied to human in vitro uptake transport data using valsartan as a probe substrate. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used for in vitro uptake experiments. The uptake rate of valsartan was higher for rat hepatocytes (
K
m,u
= 28.4 ± 3.7 μM,
V
max
= 1318 ± 176 pmol/mg/min and
P
dif
= 1.21 ± 0.42 μl/mg/min) compared to human hepatocytes (
K
m,u
= 44.4 ± 14.6 μM,
V
max
= 304 ± 85 pmol/mg/min and
P
dif
= 0.724 ± 0.271 μl/mg/min). OATP1B1 and 1B3 parameters were correlated to human hepatocyte data using experimentally established relative activity factors (RAF). Resulting PBPK simulations using those in vitro data were compared for plasma (human and rat) and bile (rat) concentration–time profiles following i.v. bolus administration of valsartan. An uncertainty analysis indicated that the scaled in vitro uptake clearance had to be adjusted with an additional empirical scaling factor of 5 to match the plasma concentrations and biliary excretion profiles. Applying this model, plasma clearances (CL
P
) for rat and human were predicted within two-fold relative to predictions based on respective in vitro data. The corrected hepatic uptake transport kinetic parameters enabled the prediction of valsartan in vivo PK profiles and plasma clearances, using PBPK modeling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro. More data are needed to support more general applications of the proposed approach including its use for metabolized compounds. |
| doi_str_mv | 10.1007/s10928-009-9139-3 |
| format | article |
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K
m,u
= 28.4 ± 3.7 μM,
V
max
= 1318 ± 176 pmol/mg/min and
P
dif
= 1.21 ± 0.42 μl/mg/min) compared to human hepatocytes (
K
m,u
= 44.4 ± 14.6 μM,
V
max
= 304 ± 85 pmol/mg/min and
P
dif
= 0.724 ± 0.271 μl/mg/min). OATP1B1 and 1B3 parameters were correlated to human hepatocyte data using experimentally established relative activity factors (RAF). Resulting PBPK simulations using those in vitro data were compared for plasma (human and rat) and bile (rat) concentration–time profiles following i.v. bolus administration of valsartan. An uncertainty analysis indicated that the scaled in vitro uptake clearance had to be adjusted with an additional empirical scaling factor of 5 to match the plasma concentrations and biliary excretion profiles. Applying this model, plasma clearances (CL
P
) for rat and human were predicted within two-fold relative to predictions based on respective in vitro data. The corrected hepatic uptake transport kinetic parameters enabled the prediction of valsartan in vivo PK profiles and plasma clearances, using PBPK modeling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro. More data are needed to support more general applications of the proposed approach including its use for metabolized compounds.</description><identifier>ISSN: 1567-567X</identifier><identifier>EISSN: 1573-8744</identifier><identifier>DOI: 10.1007/s10928-009-9139-3</identifier><identifier>PMID: 19936896</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Administration, Oral ; Adult ; Aged ; Angiotensin II Type 1 Receptor Blockers - administration & dosage ; Angiotensin II Type 1 Receptor Blockers - blood ; Angiotensin II Type 1 Receptor Blockers - pharmacokinetics ; Animals ; Bile - metabolism ; Biochemistry ; Biological Transport, Active ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Biomedicine ; CHO Cells ; Cricetinae ; Cricetulus ; Cross-Over Studies ; Drug Interactions ; Female ; Hepatocytes - metabolism ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Models, Biological ; Organic Anion Transporters - genetics ; Organic Anion Transporters - metabolism ; Organic Anion Transporters, Sodium-Independent - metabolism ; Pharmacology/Toxicology ; Pharmacy ; Randomized Controlled Trials as Topic ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Reproducibility of Results ; Solute Carrier Organic Anion Transporter Family Member 1b1 ; Solute Carrier Organic Anion Transporter Family Member 1B3 ; Species Specificity ; Tetrazoles - administration & dosage ; Tetrazoles - blood ; Tetrazoles - pharmacokinetics ; Transfection ; Valine - administration & dosage ; Valine - analogs & derivatives ; Valine - blood ; Valine - pharmacokinetics ; Valsartan ; Veterinary Medicine/Veterinary Science</subject><ispartof>Journal of pharmacokinetics and pharmacodynamics, 2009-12, Vol.36 (6), p.585-611</ispartof><rights>Springer Science+Business Media, LLC 2009</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c436t-8753439f31637494ee86c1ead881a033ad7daf25b51066c1dff0b6dc29fa9c7c3</citedby><cites>FETCH-LOGICAL-c436t-8753439f31637494ee86c1ead881a033ad7daf25b51066c1dff0b6dc29fa9c7c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19936896$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Poirier, Agnès</creatorcontrib><creatorcontrib>Cascais, Anne-Christine</creatorcontrib><creatorcontrib>Funk, Christoph</creatorcontrib><creatorcontrib>Lavé, Thierry</creatorcontrib><title>Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data</title><title>Journal of pharmacokinetics and pharmacodynamics</title><addtitle>J Pharmacokinet Pharmacodyn</addtitle><addtitle>J Pharmacokinet Pharmacodyn</addtitle><description>The aim of this study was to evaluate a strategy based on a physiologically based pharmacokinetic (PBPK) model for the prediction of PK profiles in human using in vitro data when elimination of compounds relies on active transport processes. The strategy was first applied to rat in vivo and in vitro data in order to refine the PBPK model. The model could then be applied to human in vitro uptake transport data using valsartan as a probe substrate. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used for in vitro uptake experiments. The uptake rate of valsartan was higher for rat hepatocytes (
K
m,u
= 28.4 ± 3.7 μM,
V
max
= 1318 ± 176 pmol/mg/min and
P
dif
= 1.21 ± 0.42 μl/mg/min) compared to human hepatocytes (
K
m,u
= 44.4 ± 14.6 μM,
V
max
= 304 ± 85 pmol/mg/min and
P
dif
= 0.724 ± 0.271 μl/mg/min). OATP1B1 and 1B3 parameters were correlated to human hepatocyte data using experimentally established relative activity factors (RAF). Resulting PBPK simulations using those in vitro data were compared for plasma (human and rat) and bile (rat) concentration–time profiles following i.v. bolus administration of valsartan. An uncertainty analysis indicated that the scaled in vitro uptake clearance had to be adjusted with an additional empirical scaling factor of 5 to match the plasma concentrations and biliary excretion profiles. Applying this model, plasma clearances (CL
P
) for rat and human were predicted within two-fold relative to predictions based on respective in vitro data. The corrected hepatic uptake transport kinetic parameters enabled the prediction of valsartan in vivo PK profiles and plasma clearances, using PBPK modeling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro. More data are needed to support more general applications of the proposed approach including its use for metabolized compounds.</description><subject>Administration, Oral</subject><subject>Adult</subject><subject>Aged</subject><subject>Angiotensin II Type 1 Receptor Blockers - administration & dosage</subject><subject>Angiotensin II Type 1 Receptor Blockers - blood</subject><subject>Angiotensin II Type 1 Receptor Blockers - pharmacokinetics</subject><subject>Animals</subject><subject>Bile - metabolism</subject><subject>Biochemistry</subject><subject>Biological Transport, Active</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering and Bioengineering</subject><subject>Biomedicine</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cross-Over Studies</subject><subject>Drug Interactions</subject><subject>Female</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Injections, Intravenous</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Models, Biological</subject><subject>Organic Anion Transporters - genetics</subject><subject>Organic Anion Transporters - metabolism</subject><subject>Organic Anion Transporters, Sodium-Independent - metabolism</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacy</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rats, Wistar</subject><subject>Reproducibility of Results</subject><subject>Solute Carrier Organic Anion Transporter Family Member 1b1</subject><subject>Solute Carrier Organic Anion Transporter Family Member 1B3</subject><subject>Species Specificity</subject><subject>Tetrazoles - administration & dosage</subject><subject>Tetrazoles - blood</subject><subject>Tetrazoles - pharmacokinetics</subject><subject>Transfection</subject><subject>Valine - administration & dosage</subject><subject>Valine - analogs & derivatives</subject><subject>Valine - blood</subject><subject>Valine - pharmacokinetics</subject><subject>Valsartan</subject><subject>Veterinary Medicine/Veterinary Science</subject><issn>1567-567X</issn><issn>1573-8744</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNp1UEtLxDAQDqK46-oP8CLBezVp0rQ5yuILFvSg4C2kebjd3TY1SRf896Z2wZOHYYb5HjN8AFxidIMRKm8DRjyvMoR4xjHhGTkCc1yUJKtKSo_HmZVZqo8ZOAthgxBmRY5OwQxzTljF2RyoV290o2LjOugs7NfSt1K5bdOZ2CjYe2ebnRmhvdwF6aPsYNPB9dCmoZbBaOh-N_smegeHPsqtgdHLLvTOR6hllOfgxCaxuTj0BXh_uH9bPmWrl8fn5d0qU5SwmJ4uCCXcEsxISTk1pmIKG6mrCktEiNSlljYv6gIjlhBtLaqZVjm3kqtSkQW4nnzT11-DCVFs3OC7dFLkOcU5piVNJDyRlHcheGNF75tW-m-BkRhTFVOqIqUqxlQFSZqrg_FQt0b_KQ4xJkI-EUKCuk_j_y7_7_oDwaKDqw</recordid><startdate>20091201</startdate><enddate>20091201</enddate><creator>Poirier, Agnès</creator><creator>Cascais, Anne-Christine</creator><creator>Funk, Christoph</creator><creator>Lavé, Thierry</creator><general>Springer US</general><general>Springer Nature B.V</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>3V.</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20091201</creationdate><title>Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data</title><author>Poirier, Agnès ; Cascais, Anne-Christine ; Funk, Christoph ; Lavé, Thierry</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c436t-8753439f31637494ee86c1ead881a033ad7daf25b51066c1dff0b6dc29fa9c7c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Administration, Oral</topic><topic>Adult</topic><topic>Aged</topic><topic>Angiotensin II Type 1 Receptor Blockers - administration & dosage</topic><topic>Angiotensin II Type 1 Receptor Blockers - blood</topic><topic>Angiotensin II Type 1 Receptor Blockers - pharmacokinetics</topic><topic>Animals</topic><topic>Bile - metabolism</topic><topic>Biochemistry</topic><topic>Biological Transport, Active</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering and Bioengineering</topic><topic>Biomedicine</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cross-Over Studies</topic><topic>Drug Interactions</topic><topic>Female</topic><topic>Hepatocytes - metabolism</topic><topic>Humans</topic><topic>Injections, Intravenous</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Models, Biological</topic><topic>Organic Anion Transporters - genetics</topic><topic>Organic Anion Transporters - metabolism</topic><topic>Organic Anion Transporters, Sodium-Independent - metabolism</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Randomized Controlled Trials as Topic</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Rats, Wistar</topic><topic>Reproducibility of Results</topic><topic>Solute Carrier Organic Anion Transporter Family Member 1b1</topic><topic>Solute Carrier Organic Anion Transporter Family Member 1B3</topic><topic>Species Specificity</topic><topic>Tetrazoles - administration & dosage</topic><topic>Tetrazoles - blood</topic><topic>Tetrazoles - pharmacokinetics</topic><topic>Transfection</topic><topic>Valine - administration & dosage</topic><topic>Valine - analogs & derivatives</topic><topic>Valine - blood</topic><topic>Valine - pharmacokinetics</topic><topic>Valsartan</topic><topic>Veterinary Medicine/Veterinary Science</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Poirier, Agnès</creatorcontrib><creatorcontrib>Cascais, Anne-Christine</creatorcontrib><creatorcontrib>Funk, Christoph</creatorcontrib><creatorcontrib>Lavé, Thierry</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Journal of pharmacokinetics and pharmacodynamics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Poirier, Agnès</au><au>Cascais, Anne-Christine</au><au>Funk, Christoph</au><au>Lavé, Thierry</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data</atitle><jtitle>Journal of pharmacokinetics and pharmacodynamics</jtitle><stitle>J Pharmacokinet Pharmacodyn</stitle><addtitle>J Pharmacokinet Pharmacodyn</addtitle><date>2009-12-01</date><risdate>2009</risdate><volume>36</volume><issue>6</issue><spage>585</spage><epage>611</epage><pages>585-611</pages><issn>1567-567X</issn><eissn>1573-8744</eissn><abstract>The aim of this study was to evaluate a strategy based on a physiologically based pharmacokinetic (PBPK) model for the prediction of PK profiles in human using in vitro data when elimination of compounds relies on active transport processes. The strategy was first applied to rat in vivo and in vitro data in order to refine the PBPK model. The model could then be applied to human in vitro uptake transport data using valsartan as a probe substrate. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used for in vitro uptake experiments. The uptake rate of valsartan was higher for rat hepatocytes (
K
m,u
= 28.4 ± 3.7 μM,
V
max
= 1318 ± 176 pmol/mg/min and
P
dif
= 1.21 ± 0.42 μl/mg/min) compared to human hepatocytes (
K
m,u
= 44.4 ± 14.6 μM,
V
max
= 304 ± 85 pmol/mg/min and
P
dif
= 0.724 ± 0.271 μl/mg/min). OATP1B1 and 1B3 parameters were correlated to human hepatocyte data using experimentally established relative activity factors (RAF). Resulting PBPK simulations using those in vitro data were compared for plasma (human and rat) and bile (rat) concentration–time profiles following i.v. bolus administration of valsartan. An uncertainty analysis indicated that the scaled in vitro uptake clearance had to be adjusted with an additional empirical scaling factor of 5 to match the plasma concentrations and biliary excretion profiles. Applying this model, plasma clearances (CL
P
) for rat and human were predicted within two-fold relative to predictions based on respective in vitro data. The corrected hepatic uptake transport kinetic parameters enabled the prediction of valsartan in vivo PK profiles and plasma clearances, using PBPK modeling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro. More data are needed to support more general applications of the proposed approach including its use for metabolized compounds.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>19936896</pmid><doi>10.1007/s10928-009-9139-3</doi><tpages>27</tpages></addata></record> |
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| ispartof | Journal of pharmacokinetics and pharmacodynamics, 2009-12, Vol.36 (6), p.585-611 |
| issn | 1567-567X 1573-8744 |
| language | eng |
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| subjects | Administration, Oral Adult Aged Angiotensin II Type 1 Receptor Blockers - administration & dosage Angiotensin II Type 1 Receptor Blockers - blood Angiotensin II Type 1 Receptor Blockers - pharmacokinetics Animals Bile - metabolism Biochemistry Biological Transport, Active Biomedical and Life Sciences Biomedical Engineering and Bioengineering Biomedicine CHO Cells Cricetinae Cricetulus Cross-Over Studies Drug Interactions Female Hepatocytes - metabolism Humans Injections, Intravenous Male Middle Aged Models, Biological Organic Anion Transporters - genetics Organic Anion Transporters - metabolism Organic Anion Transporters, Sodium-Independent - metabolism Pharmacology/Toxicology Pharmacy Randomized Controlled Trials as Topic Rats Rats, Sprague-Dawley Rats, Wistar Reproducibility of Results Solute Carrier Organic Anion Transporter Family Member 1b1 Solute Carrier Organic Anion Transporter Family Member 1B3 Species Specificity Tetrazoles - administration & dosage Tetrazoles - blood Tetrazoles - pharmacokinetics Transfection Valine - administration & dosage Valine - analogs & derivatives Valine - blood Valine - pharmacokinetics Valsartan Veterinary Medicine/Veterinary Science |
| title | Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data |
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