siRNA-Mediated Knockdown of P450 Oxidoreductase in Rats: A Tool to Reduce Metabolism by CYPs and Increase Exposure of High Clearance Compounds
ABSTRACT Purpose To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism in vivo , with the aim of improving plasma exposure of these drugs. Methods siRNA against the PO...
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| Veröffentlicht in: | Pharmaceutical research 2014-12, Vol.31 (12), p.3445-3460 |
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| creator | Burke, Rob S. Somasuntharam, Inthirai Rearden, Paul Brown, Duncan Deshmukh, Sujal V. DiPietro, Martha A. DiMuzio, Jillian Eisenhandler, Roy Fauty, Scott E. Gibson, Christopher Gindy, Marian E. Hamilton, Kelly A. Knemeyer, Ian Koeplinger, Kenneth A. Kwon, Hae Won Lifsted, Traci Q. Menzel, Karsten Patel, Mihir Pudvah, Nicole Rudd, Deanne Jackson Seitzer, Jessica Strapps, Walter R. Prueksaritanont, Thomayant Thompson, Charles D. Hochman, Jerome H. Carr, Brian A. |
| description | ABSTRACT
Purpose
To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism
in vivo
, with the aim of improving plasma exposure of these drugs.
Methods
siRNA against the POR gene was delivered using lipid nanoparticles (LNPs) into rats. The time course of POR mRNA knockdown, POR protein knockdown, and loss of POR enzyme activity was monitored. The rat livers were harvested to produce microsomes to determine the impact of POR knockdown on the metabolism of several probe substrates. Midazolam (a CYP3A substrate with high intrinsic clearance) was administered into LNP-treated rats to determine the impact of POR knockdown on midazolam pharmacokinetics.
Results
Hepatic POR mRNA and protein levels were significantly reduced by administering siRNA and the maximum POR enzyme activity reduction (~85%) occurred 2 weeks post-dose.
In vitro
analysis showed significant reductions in metabolism of probe substrates due to POR knockdown in liver, and
in vivo
POR knockdown resulted in greater than 10-fold increases in midazolam plasma concentrations following oral dosing.
Conclusions
Anti-POR siRNA can be used to significantly reduce hepatic metabolism by various CYPs as well as greatly increase the bioavailability of high clearance compounds following an oral dose, thus enabling it to be used as a tool to increase drug exposure
in vivo
. |
| doi_str_mv | 10.1007/s11095-014-1433-0 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1660385829</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3485873331</sourcerecordid><originalsourceid>FETCH-LOGICAL-c475t-5768ef878dc6a6528e94fabe2842003c4ecc62040385bdd1711812687951dfdd3</originalsourceid><addsrcrecordid>eNp1kcFu1DAQhi0EotvCA3BBlrhwCcw4TuxwW0WlrWhptSoSnCLHnpSUrL3YiWhfgmcm0RaEkDjNYb7vn5F-xl4gvEEA9TYhQlVkgDJDmecZPGIrLFSeVSA_P2YrUEJmWkk8YIcp3QKAxko-ZQdCVhoElCv2M_Wbj-vsglxvRnL8gw_2mws_PA8dv5IF8Mu73oVIbrKjScR7zzdmTO_4ml-HMPAx8M2yJH5Bo2nD0Kctb-95_eUqceMdP_M20mIe3-1CmiItyaf9zVdeD2Si8bNah-0uTN6lZ-xJZ4ZEzx_mEfv0_vi6Ps3OL0_O6vV5ZqUqxqxQpaZOK-1sacpCaKpkZ1oSWgqA3EqythQgIddF6xwqRI2i1Koq0HXO5Ufs9T53F8P3idLYbPtkaRiMpzClBstycbWoZvTVP-htmKKfv5spgUphqfVM4Z6yMaQUqWt2sd-aeN8gNEtZzb6sZi6rWcpqYHZePiRP7ZbcH-N3OzMg9kCaV_6G4l-n_5v6C26JnWs</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1621771688</pqid></control><display><type>article</type><title>siRNA-Mediated Knockdown of P450 Oxidoreductase in Rats: A Tool to Reduce Metabolism by CYPs and Increase Exposure of High Clearance Compounds</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Burke, Rob S. ; Somasuntharam, Inthirai ; Rearden, Paul ; Brown, Duncan ; Deshmukh, Sujal V. ; DiPietro, Martha A. ; DiMuzio, Jillian ; Eisenhandler, Roy ; Fauty, Scott E. ; Gibson, Christopher ; Gindy, Marian E. ; Hamilton, Kelly A. ; Knemeyer, Ian ; Koeplinger, Kenneth A. ; Kwon, Hae Won ; Lifsted, Traci Q. ; Menzel, Karsten ; Patel, Mihir ; Pudvah, Nicole ; Rudd, Deanne Jackson ; Seitzer, Jessica ; Strapps, Walter R. ; Prueksaritanont, Thomayant ; Thompson, Charles D. ; Hochman, Jerome H. ; Carr, Brian A.</creator><creatorcontrib>Burke, Rob S. ; Somasuntharam, Inthirai ; Rearden, Paul ; Brown, Duncan ; Deshmukh, Sujal V. ; DiPietro, Martha A. ; DiMuzio, Jillian ; Eisenhandler, Roy ; Fauty, Scott E. ; Gibson, Christopher ; Gindy, Marian E. ; Hamilton, Kelly A. ; Knemeyer, Ian ; Koeplinger, Kenneth A. ; Kwon, Hae Won ; Lifsted, Traci Q. ; Menzel, Karsten ; Patel, Mihir ; Pudvah, Nicole ; Rudd, Deanne Jackson ; Seitzer, Jessica ; Strapps, Walter R. ; Prueksaritanont, Thomayant ; Thompson, Charles D. ; Hochman, Jerome H. ; Carr, Brian A.</creatorcontrib><description>ABSTRACT
Purpose
To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism
in vivo
, with the aim of improving plasma exposure of these drugs.
Methods
siRNA against the POR gene was delivered using lipid nanoparticles (LNPs) into rats. The time course of POR mRNA knockdown, POR protein knockdown, and loss of POR enzyme activity was monitored. The rat livers were harvested to produce microsomes to determine the impact of POR knockdown on the metabolism of several probe substrates. Midazolam (a CYP3A substrate with high intrinsic clearance) was administered into LNP-treated rats to determine the impact of POR knockdown on midazolam pharmacokinetics.
Results
Hepatic POR mRNA and protein levels were significantly reduced by administering siRNA and the maximum POR enzyme activity reduction (~85%) occurred 2 weeks post-dose.
In vitro
analysis showed significant reductions in metabolism of probe substrates due to POR knockdown in liver, and
in vivo
POR knockdown resulted in greater than 10-fold increases in midazolam plasma concentrations following oral dosing.
Conclusions
Anti-POR siRNA can be used to significantly reduce hepatic metabolism by various CYPs as well as greatly increase the bioavailability of high clearance compounds following an oral dose, thus enabling it to be used as a tool to increase drug exposure
in vivo
.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1007/s11095-014-1433-0</identifier><identifier>PMID: 24980206</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Animals ; Biochemistry ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Biomedicine ; Chemistry, Pharmaceutical ; Cytochrome P-450 Enzyme System - genetics ; Diclofenac - metabolism ; Enzymes ; Gene Knockdown Techniques - methods ; In Vitro Techniques ; Male ; Medical Law ; Metabolism ; Microsomes - drug effects ; Microsomes - enzymology ; Microsomes, Liver - drug effects ; Microsomes, Liver - enzymology ; Midazolam - metabolism ; Nanoparticles ; Pharmaceutical sciences ; Pharmacology/Toxicology ; Pharmacy ; Protein Binding ; Rats ; Research Paper ; Ribonucleic acid ; RNA ; RNA, Small Interfering - pharmacology ; Rodents</subject><ispartof>Pharmaceutical research, 2014-12, Vol.31 (12), p.3445-3460</ispartof><rights>Springer Science+Business Media New York 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-5768ef878dc6a6528e94fabe2842003c4ecc62040385bdd1711812687951dfdd3</citedby><cites>FETCH-LOGICAL-c475t-5768ef878dc6a6528e94fabe2842003c4ecc62040385bdd1711812687951dfdd3</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/s11095-014-1433-0$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11095-014-1433-0$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27922,27923,41486,42555,51317</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24980206$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Burke, Rob S.</creatorcontrib><creatorcontrib>Somasuntharam, Inthirai</creatorcontrib><creatorcontrib>Rearden, Paul</creatorcontrib><creatorcontrib>Brown, Duncan</creatorcontrib><creatorcontrib>Deshmukh, Sujal V.</creatorcontrib><creatorcontrib>DiPietro, Martha A.</creatorcontrib><creatorcontrib>DiMuzio, Jillian</creatorcontrib><creatorcontrib>Eisenhandler, Roy</creatorcontrib><creatorcontrib>Fauty, Scott E.</creatorcontrib><creatorcontrib>Gibson, Christopher</creatorcontrib><creatorcontrib>Gindy, Marian E.</creatorcontrib><creatorcontrib>Hamilton, Kelly A.</creatorcontrib><creatorcontrib>Knemeyer, Ian</creatorcontrib><creatorcontrib>Koeplinger, Kenneth A.</creatorcontrib><creatorcontrib>Kwon, Hae Won</creatorcontrib><creatorcontrib>Lifsted, Traci Q.</creatorcontrib><creatorcontrib>Menzel, Karsten</creatorcontrib><creatorcontrib>Patel, Mihir</creatorcontrib><creatorcontrib>Pudvah, Nicole</creatorcontrib><creatorcontrib>Rudd, Deanne Jackson</creatorcontrib><creatorcontrib>Seitzer, Jessica</creatorcontrib><creatorcontrib>Strapps, Walter R.</creatorcontrib><creatorcontrib>Prueksaritanont, Thomayant</creatorcontrib><creatorcontrib>Thompson, Charles D.</creatorcontrib><creatorcontrib>Hochman, Jerome H.</creatorcontrib><creatorcontrib>Carr, Brian A.</creatorcontrib><title>siRNA-Mediated Knockdown of P450 Oxidoreductase in Rats: A Tool to Reduce Metabolism by CYPs and Increase Exposure of High Clearance Compounds</title><title>Pharmaceutical research</title><addtitle>Pharm Res</addtitle><addtitle>Pharm Res</addtitle><description>ABSTRACT
Purpose
To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism
in vivo
, with the aim of improving plasma exposure of these drugs.
Methods
siRNA against the POR gene was delivered using lipid nanoparticles (LNPs) into rats. The time course of POR mRNA knockdown, POR protein knockdown, and loss of POR enzyme activity was monitored. The rat livers were harvested to produce microsomes to determine the impact of POR knockdown on the metabolism of several probe substrates. Midazolam (a CYP3A substrate with high intrinsic clearance) was administered into LNP-treated rats to determine the impact of POR knockdown on midazolam pharmacokinetics.
Results
Hepatic POR mRNA and protein levels were significantly reduced by administering siRNA and the maximum POR enzyme activity reduction (~85%) occurred 2 weeks post-dose.
In vitro
analysis showed significant reductions in metabolism of probe substrates due to POR knockdown in liver, and
in vivo
POR knockdown resulted in greater than 10-fold increases in midazolam plasma concentrations following oral dosing.
Conclusions
Anti-POR siRNA can be used to significantly reduce hepatic metabolism by various CYPs as well as greatly increase the bioavailability of high clearance compounds following an oral dose, thus enabling it to be used as a tool to increase drug exposure
in vivo
.</description><subject>Animals</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering and Bioengineering</subject><subject>Biomedicine</subject><subject>Chemistry, Pharmaceutical</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Diclofenac - metabolism</subject><subject>Enzymes</subject><subject>Gene Knockdown Techniques - methods</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Medical Law</subject><subject>Metabolism</subject><subject>Microsomes - drug effects</subject><subject>Microsomes - enzymology</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - enzymology</subject><subject>Midazolam - metabolism</subject><subject>Nanoparticles</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacy</subject><subject>Protein Binding</subject><subject>Rats</subject><subject>Research Paper</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Small Interfering - pharmacology</subject><subject>Rodents</subject><issn>0724-8741</issn><issn>1573-904X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kcFu1DAQhi0EotvCA3BBlrhwCcw4TuxwW0WlrWhptSoSnCLHnpSUrL3YiWhfgmcm0RaEkDjNYb7vn5F-xl4gvEEA9TYhQlVkgDJDmecZPGIrLFSeVSA_P2YrUEJmWkk8YIcp3QKAxko-ZQdCVhoElCv2M_Wbj-vsglxvRnL8gw_2mws_PA8dv5IF8Mu73oVIbrKjScR7zzdmTO_4ml-HMPAx8M2yJH5Bo2nD0Kctb-95_eUqceMdP_M20mIe3-1CmiItyaf9zVdeD2Si8bNah-0uTN6lZ-xJZ4ZEzx_mEfv0_vi6Ps3OL0_O6vV5ZqUqxqxQpaZOK-1sacpCaKpkZ1oSWgqA3EqythQgIddF6xwqRI2i1Koq0HXO5Ufs9T53F8P3idLYbPtkaRiMpzClBstycbWoZvTVP-htmKKfv5spgUphqfVM4Z6yMaQUqWt2sd-aeN8gNEtZzb6sZi6rWcpqYHZePiRP7ZbcH-N3OzMg9kCaV_6G4l-n_5v6C26JnWs</recordid><startdate>20141201</startdate><enddate>20141201</enddate><creator>Burke, Rob S.</creator><creator>Somasuntharam, Inthirai</creator><creator>Rearden, Paul</creator><creator>Brown, Duncan</creator><creator>Deshmukh, Sujal V.</creator><creator>DiPietro, Martha A.</creator><creator>DiMuzio, Jillian</creator><creator>Eisenhandler, Roy</creator><creator>Fauty, Scott E.</creator><creator>Gibson, Christopher</creator><creator>Gindy, Marian E.</creator><creator>Hamilton, Kelly A.</creator><creator>Knemeyer, Ian</creator><creator>Koeplinger, Kenneth A.</creator><creator>Kwon, Hae Won</creator><creator>Lifsted, Traci Q.</creator><creator>Menzel, Karsten</creator><creator>Patel, Mihir</creator><creator>Pudvah, Nicole</creator><creator>Rudd, Deanne Jackson</creator><creator>Seitzer, Jessica</creator><creator>Strapps, Walter R.</creator><creator>Prueksaritanont, Thomayant</creator><creator>Thompson, Charles D.</creator><creator>Hochman, Jerome H.</creator><creator>Carr, Brian A.</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>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>7U7</scope><scope>C1K</scope></search><sort><creationdate>20141201</creationdate><title>siRNA-Mediated Knockdown of P450 Oxidoreductase in Rats: A Tool to Reduce Metabolism by CYPs and Increase Exposure of High Clearance Compounds</title><author>Burke, Rob S. ; Somasuntharam, Inthirai ; Rearden, Paul ; Brown, Duncan ; Deshmukh, Sujal V. ; DiPietro, Martha A. ; DiMuzio, Jillian ; Eisenhandler, Roy ; Fauty, Scott E. ; Gibson, Christopher ; Gindy, Marian E. ; Hamilton, Kelly A. ; Knemeyer, Ian ; Koeplinger, Kenneth A. ; Kwon, Hae Won ; Lifsted, Traci Q. ; Menzel, Karsten ; Patel, Mihir ; Pudvah, Nicole ; Rudd, Deanne Jackson ; Seitzer, Jessica ; Strapps, Walter R. ; Prueksaritanont, Thomayant ; Thompson, Charles D. ; Hochman, Jerome H. ; Carr, Brian A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-5768ef878dc6a6528e94fabe2842003c4ecc62040385bdd1711812687951dfdd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering and Bioengineering</topic><topic>Biomedicine</topic><topic>Chemistry, Pharmaceutical</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Diclofenac - metabolism</topic><topic>Enzymes</topic><topic>Gene Knockdown Techniques - methods</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Medical Law</topic><topic>Metabolism</topic><topic>Microsomes - drug effects</topic><topic>Microsomes - enzymology</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - enzymology</topic><topic>Midazolam - metabolism</topic><topic>Nanoparticles</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Protein Binding</topic><topic>Rats</topic><topic>Research Paper</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Small Interfering - pharmacology</topic><topic>Rodents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Burke, Rob S.</creatorcontrib><creatorcontrib>Somasuntharam, Inthirai</creatorcontrib><creatorcontrib>Rearden, Paul</creatorcontrib><creatorcontrib>Brown, Duncan</creatorcontrib><creatorcontrib>Deshmukh, Sujal V.</creatorcontrib><creatorcontrib>DiPietro, Martha A.</creatorcontrib><creatorcontrib>DiMuzio, Jillian</creatorcontrib><creatorcontrib>Eisenhandler, Roy</creatorcontrib><creatorcontrib>Fauty, Scott E.</creatorcontrib><creatorcontrib>Gibson, Christopher</creatorcontrib><creatorcontrib>Gindy, Marian E.</creatorcontrib><creatorcontrib>Hamilton, Kelly A.</creatorcontrib><creatorcontrib>Knemeyer, Ian</creatorcontrib><creatorcontrib>Koeplinger, Kenneth A.</creatorcontrib><creatorcontrib>Kwon, Hae Won</creatorcontrib><creatorcontrib>Lifsted, Traci Q.</creatorcontrib><creatorcontrib>Menzel, Karsten</creatorcontrib><creatorcontrib>Patel, Mihir</creatorcontrib><creatorcontrib>Pudvah, Nicole</creatorcontrib><creatorcontrib>Rudd, Deanne Jackson</creatorcontrib><creatorcontrib>Seitzer, Jessica</creatorcontrib><creatorcontrib>Strapps, Walter R.</creatorcontrib><creatorcontrib>Prueksaritanont, Thomayant</creatorcontrib><creatorcontrib>Thompson, Charles D.</creatorcontrib><creatorcontrib>Hochman, Jerome H.</creatorcontrib><creatorcontrib>Carr, Brian A.</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>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>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Pharmaceutical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Burke, Rob S.</au><au>Somasuntharam, Inthirai</au><au>Rearden, Paul</au><au>Brown, Duncan</au><au>Deshmukh, Sujal V.</au><au>DiPietro, Martha A.</au><au>DiMuzio, Jillian</au><au>Eisenhandler, Roy</au><au>Fauty, Scott E.</au><au>Gibson, Christopher</au><au>Gindy, Marian E.</au><au>Hamilton, Kelly A.</au><au>Knemeyer, Ian</au><au>Koeplinger, Kenneth A.</au><au>Kwon, Hae Won</au><au>Lifsted, Traci Q.</au><au>Menzel, Karsten</au><au>Patel, Mihir</au><au>Pudvah, Nicole</au><au>Rudd, Deanne Jackson</au><au>Seitzer, Jessica</au><au>Strapps, Walter R.</au><au>Prueksaritanont, Thomayant</au><au>Thompson, Charles D.</au><au>Hochman, Jerome H.</au><au>Carr, Brian A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>siRNA-Mediated Knockdown of P450 Oxidoreductase in Rats: A Tool to Reduce Metabolism by CYPs and Increase Exposure of High Clearance Compounds</atitle><jtitle>Pharmaceutical research</jtitle><stitle>Pharm Res</stitle><addtitle>Pharm Res</addtitle><date>2014-12-01</date><risdate>2014</risdate><volume>31</volume><issue>12</issue><spage>3445</spage><epage>3460</epage><pages>3445-3460</pages><issn>0724-8741</issn><eissn>1573-904X</eissn><abstract>ABSTRACT
Purpose
To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism
in vivo
, with the aim of improving plasma exposure of these drugs.
Methods
siRNA against the POR gene was delivered using lipid nanoparticles (LNPs) into rats. The time course of POR mRNA knockdown, POR protein knockdown, and loss of POR enzyme activity was monitored. The rat livers were harvested to produce microsomes to determine the impact of POR knockdown on the metabolism of several probe substrates. Midazolam (a CYP3A substrate with high intrinsic clearance) was administered into LNP-treated rats to determine the impact of POR knockdown on midazolam pharmacokinetics.
Results
Hepatic POR mRNA and protein levels were significantly reduced by administering siRNA and the maximum POR enzyme activity reduction (~85%) occurred 2 weeks post-dose.
In vitro
analysis showed significant reductions in metabolism of probe substrates due to POR knockdown in liver, and
in vivo
POR knockdown resulted in greater than 10-fold increases in midazolam plasma concentrations following oral dosing.
Conclusions
Anti-POR siRNA can be used to significantly reduce hepatic metabolism by various CYPs as well as greatly increase the bioavailability of high clearance compounds following an oral dose, thus enabling it to be used as a tool to increase drug exposure
in vivo
.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>24980206</pmid><doi>10.1007/s11095-014-1433-0</doi><tpages>16</tpages></addata></record> |
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| ispartof | Pharmaceutical research, 2014-12, Vol.31 (12), p.3445-3460 |
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| subjects | Animals Biochemistry Biomedical and Life Sciences Biomedical Engineering and Bioengineering Biomedicine Chemistry, Pharmaceutical Cytochrome P-450 Enzyme System - genetics Diclofenac - metabolism Enzymes Gene Knockdown Techniques - methods In Vitro Techniques Male Medical Law Metabolism Microsomes - drug effects Microsomes - enzymology Microsomes, Liver - drug effects Microsomes, Liver - enzymology Midazolam - metabolism Nanoparticles Pharmaceutical sciences Pharmacology/Toxicology Pharmacy Protein Binding Rats Research Paper Ribonucleic acid RNA RNA, Small Interfering - pharmacology Rodents |
| title | siRNA-Mediated Knockdown of P450 Oxidoreductase in Rats: A Tool to Reduce Metabolism by CYPs and Increase Exposure of High Clearance Compounds |
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