In Vivo and Ex Vivo Inhibition of Spinal Nerve Ligation-Induced Ectopic Activity by Sodium Channel Blockers Correlate to In Vitro Inhibition of NaV1.7 and Clinical Efficacy: A Pharmacokinetic-Pharmacodynamic Translational Approach
Purpose In vivo and ex vivo inhibition of ectopic activity of clinically used and newly developed sodium channel (NaV) blockers were quantified in the rat spinal nerve ligation (SNL) model using a pharmacokinetic-pharmacodynamic (PKPD) approach and correlated to in vitro NaV1.7 channel inhibition an...
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| Veröffentlicht in: | Pharmaceutical research 2013-05, Vol.30 (5), p.1409-1422 |
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| creator | Kalezic, Ivana Luo, Lei Lund, Per-Eric Eriksson, Anders B Bueters, Tjerk Visser, Sandra A. G. |
| description | Purpose
In vivo
and
ex vivo
inhibition of ectopic activity of clinically used and newly developed sodium channel (NaV) blockers were quantified in the rat spinal nerve ligation (SNL) model using a pharmacokinetic-pharmacodynamic (PKPD) approach and correlated to
in vitro
NaV1.7 channel inhibition and clinical effective concentrations.
Methods
In vivo
, drug exposure and inhibition of ectopic activity were assessed in anaesthetized SNL rats at two dose levels.
Ex vivo
, compounds were applied at increasing concentrations to dorsal root ganglias isolated from SNL rats. The inhibitory potency (
IC
50
) was estimated using PKPD analysis.
In vitro IC
50
was estimated using an electrophysiology-based assay using recombinant rat and human NaV1.7 expressing HEK293 cells.
Results
In vivo
and
ex vivo
inhibition of ectopic activity correlated well with the
in vitro
inhibition on the rat NaV1.7 channel. The estimated
IC
50s
for inhibition of ectopic activity in the SNL model occurred at similar unbound concentrations as clinical effective concentrations in humans.
Conclusions
Inhibition of ectopic activity in the SNL model could be useful in predicting clinical effective concentrations for novel sodium channel blockers. In addition,
in vitro
potency could be used for screening, characterization and selection of compounds, thereby reducing the need for
in vivo
testing. |
| doi_str_mv | 10.1007/s11095-013-0979-6 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1419360765</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1324390363</sourcerecordid><originalsourceid>FETCH-LOGICAL-c461t-afeed7b66f98aa74935dadc9427886ff979289e1d94df7fb376845dd9aac7f1d3</originalsourceid><addsrcrecordid>eNqFkttu1DAQhiMEokvhAbhBlhASNyl27MQxd0u0wEqrgtRScRfN-tB1m9hbO1mxL8xz4D0UUCXE1diab-Yfj_8se0nwGcGYv4uEYFHmmNAcCy7y6lE2ISWnucDs--NsgnnB8pozcpI9i_EGY1wTwZ5mJwWlnJSETbKfc4eu7MYjcArNfhzOc7eySztY75A36GJtHXToXIeNRgt7DbtEPndqlDrVyMGvrURTOdiNHbZouUUXXtmxR80KnNMd-tB5eatDRI0PQXcwaDTsRJLYEB6qncMVOeP7cZrOOiuT9MyYFOX2PZqirysIPUh_a50erMzv72rroE9zXAZwsdvPmCqn63XwIFfPsycGuqhfHONp9u3j7LL5nC--fJo300UuWUWGHIzWii-ryogagDNBSwVKClbwuq6MSUsuaqGJEkwZbpaUVzUrlRIAkhui6Gn29tA3yd6NOg5tb6PUXQdO-zG2hBFBK8yr8v8oLRgVmFY0oa8foDd-DOl9e4oKXgtWJYocKBl8jEGbdh1sD2HbEtzu_NIe_NImv7Q7v7S7mlfHzuOy1-p3xb1BEvDmCEBMX2HSdqWNfzhOaYnLInHFgYsp5a51-GvEf6r_Ap5z2qE</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1323978946</pqid></control><display><type>article</type><title>In Vivo and Ex Vivo Inhibition of Spinal Nerve Ligation-Induced Ectopic Activity by Sodium Channel Blockers Correlate to In Vitro Inhibition of NaV1.7 and Clinical Efficacy: A Pharmacokinetic-Pharmacodynamic Translational Approach</title><source>MEDLINE</source><source>SpringerNature Journals</source><creator>Kalezic, Ivana ; Luo, Lei ; Lund, Per-Eric ; Eriksson, Anders B ; Bueters, Tjerk ; Visser, Sandra A. G.</creator><creatorcontrib>Kalezic, Ivana ; Luo, Lei ; Lund, Per-Eric ; Eriksson, Anders B ; Bueters, Tjerk ; Visser, Sandra A. G.</creatorcontrib><description>Purpose
In vivo
and
ex vivo
inhibition of ectopic activity of clinically used and newly developed sodium channel (NaV) blockers were quantified in the rat spinal nerve ligation (SNL) model using a pharmacokinetic-pharmacodynamic (PKPD) approach and correlated to
in vitro
NaV1.7 channel inhibition and clinical effective concentrations.
Methods
In vivo
, drug exposure and inhibition of ectopic activity were assessed in anaesthetized SNL rats at two dose levels.
Ex vivo
, compounds were applied at increasing concentrations to dorsal root ganglias isolated from SNL rats. The inhibitory potency (
IC
50
) was estimated using PKPD analysis.
In vitro IC
50
was estimated using an electrophysiology-based assay using recombinant rat and human NaV1.7 expressing HEK293 cells.
Results
In vivo
and
ex vivo
inhibition of ectopic activity correlated well with the
in vitro
inhibition on the rat NaV1.7 channel. The estimated
IC
50s
for inhibition of ectopic activity in the SNL model occurred at similar unbound concentrations as clinical effective concentrations in humans.
Conclusions
Inhibition of ectopic activity in the SNL model could be useful in predicting clinical effective concentrations for novel sodium channel blockers. In addition,
in vitro
potency could be used for screening, characterization and selection of compounds, thereby reducing the need for
in vivo
testing.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1007/s11095-013-0979-6</identifier><identifier>PMID: 23371514</identifier><identifier>CODEN: PHREEB</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Animals ; Biochemistry ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Biomedicine ; HEK293 Cells ; Humans ; Kinetics ; Ligation ; Male ; Medical Law ; Medical sciences ; NAV1.7 Voltage-Gated Sodium Channel - metabolism ; Neuralgia - drug therapy ; Neurology ; Pharmacology ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Pharmacy ; Rats ; Rats, Sprague-Dawley ; Research Paper ; Rodents ; Sodium Channel Blockers - blood ; Sodium Channel Blockers - pharmacology ; Spinal Nerves - drug effects ; Spinal Nerves - surgery ; Spine</subject><ispartof>Pharmaceutical research, 2013-05, Vol.30 (5), p.1409-1422</ispartof><rights>Springer Science+Business Media New York 2013</rights><rights>2014 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c461t-afeed7b66f98aa74935dadc9427886ff979289e1d94df7fb376845dd9aac7f1d3</citedby><cites>FETCH-LOGICAL-c461t-afeed7b66f98aa74935dadc9427886ff979289e1d94df7fb376845dd9aac7f1d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11095-013-0979-6$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11095-013-0979-6$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,782,786,27933,27934,41497,42566,51328</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27335052$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23371514$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kalezic, Ivana</creatorcontrib><creatorcontrib>Luo, Lei</creatorcontrib><creatorcontrib>Lund, Per-Eric</creatorcontrib><creatorcontrib>Eriksson, Anders B</creatorcontrib><creatorcontrib>Bueters, Tjerk</creatorcontrib><creatorcontrib>Visser, Sandra A. G.</creatorcontrib><title>In Vivo and Ex Vivo Inhibition of Spinal Nerve Ligation-Induced Ectopic Activity by Sodium Channel Blockers Correlate to In Vitro Inhibition of NaV1.7 and Clinical Efficacy: A Pharmacokinetic-Pharmacodynamic Translational Approach</title><title>Pharmaceutical research</title><addtitle>Pharm Res</addtitle><addtitle>Pharm Res</addtitle><description>Purpose
In vivo
and
ex vivo
inhibition of ectopic activity of clinically used and newly developed sodium channel (NaV) blockers were quantified in the rat spinal nerve ligation (SNL) model using a pharmacokinetic-pharmacodynamic (PKPD) approach and correlated to
in vitro
NaV1.7 channel inhibition and clinical effective concentrations.
Methods
In vivo
, drug exposure and inhibition of ectopic activity were assessed in anaesthetized SNL rats at two dose levels.
Ex vivo
, compounds were applied at increasing concentrations to dorsal root ganglias isolated from SNL rats. The inhibitory potency (
IC
50
) was estimated using PKPD analysis.
In vitro IC
50
was estimated using an electrophysiology-based assay using recombinant rat and human NaV1.7 expressing HEK293 cells.
Results
In vivo
and
ex vivo
inhibition of ectopic activity correlated well with the
in vitro
inhibition on the rat NaV1.7 channel. The estimated
IC
50s
for inhibition of ectopic activity in the SNL model occurred at similar unbound concentrations as clinical effective concentrations in humans.
Conclusions
Inhibition of ectopic activity in the SNL model could be useful in predicting clinical effective concentrations for novel sodium channel blockers. In addition,
in vitro
potency could be used for screening, characterization and selection of compounds, thereby reducing the need for
in vivo
testing.</description><subject>Animals</subject><subject>Biochemistry</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering and Bioengineering</subject><subject>Biomedicine</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Ligation</subject><subject>Male</subject><subject>Medical Law</subject><subject>Medical sciences</subject><subject>NAV1.7 Voltage-Gated Sodium Channel - metabolism</subject><subject>Neuralgia - drug therapy</subject><subject>Neurology</subject><subject>Pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacy</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Research Paper</subject><subject>Rodents</subject><subject>Sodium Channel Blockers - blood</subject><subject>Sodium Channel Blockers - pharmacology</subject><subject>Spinal Nerves - drug effects</subject><subject>Spinal Nerves - surgery</subject><subject>Spine</subject><issn>0724-8741</issn><issn>1573-904X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqFkttu1DAQhiMEokvhAbhBlhASNyl27MQxd0u0wEqrgtRScRfN-tB1m9hbO1mxL8xz4D0UUCXE1diab-Yfj_8se0nwGcGYv4uEYFHmmNAcCy7y6lE2ISWnucDs--NsgnnB8pozcpI9i_EGY1wTwZ5mJwWlnJSETbKfc4eu7MYjcArNfhzOc7eySztY75A36GJtHXToXIeNRgt7DbtEPndqlDrVyMGvrURTOdiNHbZouUUXXtmxR80KnNMd-tB5eatDRI0PQXcwaDTsRJLYEB6qncMVOeP7cZrOOiuT9MyYFOX2PZqirysIPUh_a50erMzv72rroE9zXAZwsdvPmCqn63XwIFfPsycGuqhfHONp9u3j7LL5nC--fJo300UuWUWGHIzWii-ryogagDNBSwVKClbwuq6MSUsuaqGJEkwZbpaUVzUrlRIAkhui6Gn29tA3yd6NOg5tb6PUXQdO-zG2hBFBK8yr8v8oLRgVmFY0oa8foDd-DOl9e4oKXgtWJYocKBl8jEGbdh1sD2HbEtzu_NIe_NImv7Q7v7S7mlfHzuOy1-p3xb1BEvDmCEBMX2HSdqWNfzhOaYnLInHFgYsp5a51-GvEf6r_Ap5z2qE</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Kalezic, Ivana</creator><creator>Luo, Lei</creator><creator>Lund, Per-Eric</creator><creator>Eriksson, Anders B</creator><creator>Bueters, Tjerk</creator><creator>Visser, Sandra A. G.</creator><general>Springer US</general><general>Springer</general><general>Springer Nature B.V</general><scope>IQODW</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>3V.</scope><scope>7RV</scope><scope>7TK</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>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20130501</creationdate><title>In Vivo and Ex Vivo Inhibition of Spinal Nerve Ligation-Induced Ectopic Activity by Sodium Channel Blockers Correlate to In Vitro Inhibition of NaV1.7 and Clinical Efficacy: A Pharmacokinetic-Pharmacodynamic Translational Approach</title><author>Kalezic, Ivana ; Luo, Lei ; Lund, Per-Eric ; Eriksson, Anders B ; Bueters, Tjerk ; Visser, Sandra A. G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c461t-afeed7b66f98aa74935dadc9427886ff979289e1d94df7fb376845dd9aac7f1d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Biochemistry</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering and Bioengineering</topic><topic>Biomedicine</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Ligation</topic><topic>Male</topic><topic>Medical Law</topic><topic>Medical sciences</topic><topic>NAV1.7 Voltage-Gated Sodium Channel - metabolism</topic><topic>Neuralgia - drug therapy</topic><topic>Neurology</topic><topic>Pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Research Paper</topic><topic>Rodents</topic><topic>Sodium Channel Blockers - blood</topic><topic>Sodium Channel Blockers - pharmacology</topic><topic>Spinal Nerves - drug effects</topic><topic>Spinal Nerves - surgery</topic><topic>Spine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kalezic, Ivana</creatorcontrib><creatorcontrib>Luo, Lei</creatorcontrib><creatorcontrib>Lund, Per-Eric</creatorcontrib><creatorcontrib>Eriksson, Anders B</creatorcontrib><creatorcontrib>Bueters, Tjerk</creatorcontrib><creatorcontrib>Visser, Sandra A. G.</creatorcontrib><collection>Pascal-Francis</collection><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>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>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 Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</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><collection>MEDLINE - Academic</collection><jtitle>Pharmaceutical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kalezic, Ivana</au><au>Luo, Lei</au><au>Lund, Per-Eric</au><au>Eriksson, Anders B</au><au>Bueters, Tjerk</au><au>Visser, Sandra A. G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In Vivo and Ex Vivo Inhibition of Spinal Nerve Ligation-Induced Ectopic Activity by Sodium Channel Blockers Correlate to In Vitro Inhibition of NaV1.7 and Clinical Efficacy: A Pharmacokinetic-Pharmacodynamic Translational Approach</atitle><jtitle>Pharmaceutical research</jtitle><stitle>Pharm Res</stitle><addtitle>Pharm Res</addtitle><date>2013-05-01</date><risdate>2013</risdate><volume>30</volume><issue>5</issue><spage>1409</spage><epage>1422</epage><pages>1409-1422</pages><issn>0724-8741</issn><eissn>1573-904X</eissn><coden>PHREEB</coden><abstract>Purpose
In vivo
and
ex vivo
inhibition of ectopic activity of clinically used and newly developed sodium channel (NaV) blockers were quantified in the rat spinal nerve ligation (SNL) model using a pharmacokinetic-pharmacodynamic (PKPD) approach and correlated to
in vitro
NaV1.7 channel inhibition and clinical effective concentrations.
Methods
In vivo
, drug exposure and inhibition of ectopic activity were assessed in anaesthetized SNL rats at two dose levels.
Ex vivo
, compounds were applied at increasing concentrations to dorsal root ganglias isolated from SNL rats. The inhibitory potency (
IC
50
) was estimated using PKPD analysis.
In vitro IC
50
was estimated using an electrophysiology-based assay using recombinant rat and human NaV1.7 expressing HEK293 cells.
Results
In vivo
and
ex vivo
inhibition of ectopic activity correlated well with the
in vitro
inhibition on the rat NaV1.7 channel. The estimated
IC
50s
for inhibition of ectopic activity in the SNL model occurred at similar unbound concentrations as clinical effective concentrations in humans.
Conclusions
Inhibition of ectopic activity in the SNL model could be useful in predicting clinical effective concentrations for novel sodium channel blockers. In addition,
in vitro
potency could be used for screening, characterization and selection of compounds, thereby reducing the need for
in vivo
testing.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>23371514</pmid><doi>10.1007/s11095-013-0979-6</doi><tpages>14</tpages></addata></record> |
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| ispartof | Pharmaceutical research, 2013-05, Vol.30 (5), p.1409-1422 |
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| source | MEDLINE; SpringerNature Journals |
| subjects | Animals Biochemistry Biological and medical sciences Biomedical and Life Sciences Biomedical Engineering and Bioengineering Biomedicine HEK293 Cells Humans Kinetics Ligation Male Medical Law Medical sciences NAV1.7 Voltage-Gated Sodium Channel - metabolism Neuralgia - drug therapy Neurology Pharmacology Pharmacology. Drug treatments Pharmacology/Toxicology Pharmacy Rats Rats, Sprague-Dawley Research Paper Rodents Sodium Channel Blockers - blood Sodium Channel Blockers - pharmacology Spinal Nerves - drug effects Spinal Nerves - surgery Spine |
| title | In Vivo and Ex Vivo Inhibition of Spinal Nerve Ligation-Induced Ectopic Activity by Sodium Channel Blockers Correlate to In Vitro Inhibition of NaV1.7 and Clinical Efficacy: A Pharmacokinetic-Pharmacodynamic Translational Approach |
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