Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib
Robenacoxib is a new nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration-time...
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| description | Robenacoxib is a new nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration-time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX-1 and COX-2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B₂ provided a marker of both COX-1 and COX-2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC₅₀ were 28.9 (16.4-51.1) μ m (COX-1) and 0.058 (0.010-0.340) μ m (COX-2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX-1:COX-2) were 502.3 (IC₅₀/IC₅₀), 451.6 (IC₉₅/IC₉₅) and 17.05 (IC₂₀/IC₈₀). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX-1 and 90% inhibition of COX-2. |
| doi_str_mv | 10.1111/j.1365-2885.2008.01031.x |
| format | Article |
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The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration-time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX-1 and COX-2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B₂ provided a marker of both COX-1 and COX-2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC₅₀ were 28.9 (16.4-51.1) μ m (COX-1) and 0.058 (0.010-0.340) μ m (COX-2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX-1:COX-2) were 502.3 (IC₅₀/IC₅₀), 451.6 (IC₉₅/IC₉₅) and 17.05 (IC₂₀/IC₈₀). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX-1 and 90% inhibition of COX-2.</description><identifier>ISSN: 0140-7783</identifier><identifier>EISSN: 1365-2885</identifier><identifier>DOI: 10.1111/j.1365-2885.2008.01031.x</identifier><identifier>PMID: 19161453</identifier><language>eng</language><publisher>Oxford, UK: Oxford, UK : Blackwell Publishing Ltd</publisher><subject>Animals ; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage ; Anti-Inflammatory Agents, Non-Steroidal - blood ; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Area Under Curve ; cats ; Cats - blood ; Cats - metabolism ; Cyclooxygenase 1 - metabolism ; Cyclooxygenase 2 - metabolism ; Cyclooxygenase 2 Inhibitors - administration & dosage ; Cyclooxygenase 2 Inhibitors - blood ; Cyclooxygenase 2 Inhibitors - pharmacokinetics ; Cyclooxygenase 2 Inhibitors - pharmacology ; Cyclooxygenase Inhibitors - administration & dosage ; Cyclooxygenase Inhibitors - blood ; Cyclooxygenase Inhibitors - pharmacokinetics ; Cyclooxygenase Inhibitors - pharmacology ; Dose-Response Relationship, Drug ; enzyme inhibition ; enzyme inhibitors ; Female ; in vitro studies ; Inhibitory Concentration 50 ; Injections, Intravenous - veterinary ; Injections, Subcutaneous - veterinary ; intravenous injection ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - blood ; isozymes ; Life Sciences ; lipopolysaccharides ; Male ; nonsteroidal anti-inflammatory agents ; pharmacokinetics ; prostaglandin synthase ; robenacoxib ; subcutaneous injection ; temporal variation ; Thromboxane B2 - biosynthesis ; Thromboxane B2 - blood ; Thromboxane B2 - metabolism</subject><ispartof>Journal of veterinary pharmacology and therapeutics, 2009-02, Vol.32 (1), p.31-40</ispartof><rights>2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5791-9853ca10c44d8774615ee936b92019a0fcbc8a64eef6edbeb350d476808528aa3</citedby><cites>FETCH-LOGICAL-c5791-9853ca10c44d8774615ee936b92019a0fcbc8a64eef6edbeb350d476808528aa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1365-2885.2008.01031.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1365-2885.2008.01031.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19161453$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.inrae.fr/hal-02667140$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>GIRAUDEL, J.M</creatorcontrib><creatorcontrib>TOUTAIN, P.-L</creatorcontrib><creatorcontrib>KING, J.N</creatorcontrib><creatorcontrib>LEES, P</creatorcontrib><title>Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib</title><title>Journal of veterinary pharmacology and therapeutics</title><addtitle>J Vet Pharmacol Ther</addtitle><description>Robenacoxib is a new nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration-time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX-1 and COX-2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B₂ provided a marker of both COX-1 and COX-2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC₅₀ were 28.9 (16.4-51.1) μ m (COX-1) and 0.058 (0.010-0.340) μ m (COX-2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX-1:COX-2) were 502.3 (IC₅₀/IC₅₀), 451.6 (IC₉₅/IC₉₅) and 17.05 (IC₂₀/IC₈₀). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX-1 and 90% inhibition of COX-2.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - administration & dosage</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - blood</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Area Under Curve</subject><subject>cats</subject><subject>Cats - blood</subject><subject>Cats - metabolism</subject><subject>Cyclooxygenase 1 - metabolism</subject><subject>Cyclooxygenase 2 - metabolism</subject><subject>Cyclooxygenase 2 Inhibitors - administration & dosage</subject><subject>Cyclooxygenase 2 Inhibitors - blood</subject><subject>Cyclooxygenase 2 Inhibitors - pharmacokinetics</subject><subject>Cyclooxygenase 2 Inhibitors - pharmacology</subject><subject>Cyclooxygenase Inhibitors - administration & dosage</subject><subject>Cyclooxygenase Inhibitors - blood</subject><subject>Cyclooxygenase Inhibitors - pharmacokinetics</subject><subject>Cyclooxygenase Inhibitors - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>enzyme inhibition</subject><subject>enzyme inhibitors</subject><subject>Female</subject><subject>in vitro studies</subject><subject>Inhibitory Concentration 50</subject><subject>Injections, Intravenous - veterinary</subject><subject>Injections, Subcutaneous - veterinary</subject><subject>intravenous injection</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - blood</subject><subject>isozymes</subject><subject>Life Sciences</subject><subject>lipopolysaccharides</subject><subject>Male</subject><subject>nonsteroidal anti-inflammatory agents</subject><subject>pharmacokinetics</subject><subject>prostaglandin synthase</subject><subject>robenacoxib</subject><subject>subcutaneous injection</subject><subject>temporal variation</subject><subject>Thromboxane B2 - biosynthesis</subject><subject>Thromboxane B2 - blood</subject><subject>Thromboxane B2 - metabolism</subject><issn>0140-7783</issn><issn>1365-2885</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkMtu1DAUQC0EotPCL4C3LBJ84_iRBYvRlD7QqEXqtEVsLMfjdDxk4ioObdKvx2mq6RZvfGWfcxcHIQwkhXi-blOgnCWZlCzNCJEpAUIh7d-g2f7jLZoRyEkihKQH6DCELSGESoD36AAK4JAzOkO_jl1V2dY2ndM1ds3Gla5zvsG-wmYwtff9cGcbHSx2wdvmadjZEDncbSw2usPl8DxeXM3Pj3Hry8ga37vyA3pX6TrYjy_3Ebo--b5anCXLy9PzxXyZGCYKSArJqNFATJ6vpRA5B2ZtQXlZZAQKTSpTGql5bm3F7bq0JWVknQsuiWSZ1JoeoS_T3o2u1X3rdrodlNdOnc2XanwjGecihniAyMqJNa0PobXVXgCixrBqq8Z-auynxrDqOazqo_ppUu__lju7fhVfSkbg2wQ8utoO_71Y_bj5OU7RTybfhc72e1-3fxQXVDB1e3Gqbherk9XqplC_I_954ivtlb5rXVDXV7EZJcBkDsDoP7Ddns8</recordid><startdate>200902</startdate><enddate>200902</enddate><creator>GIRAUDEL, J.M</creator><creator>TOUTAIN, P.-L</creator><creator>KING, J.N</creator><creator>LEES, P</creator><general>Oxford, UK : Blackwell Publishing Ltd</general><general>Blackwell Publishing Ltd</general><general>Wiley-Blackwell</general><scope>FBQ</scope><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>1XC</scope></search><sort><creationdate>200902</creationdate><title>Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib</title><author>GIRAUDEL, J.M ; TOUTAIN, P.-L ; KING, J.N ; LEES, P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5791-9853ca10c44d8774615ee936b92019a0fcbc8a64eef6edbeb350d476808528aa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - administration & dosage</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - blood</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Area Under Curve</topic><topic>cats</topic><topic>Cats - blood</topic><topic>Cats - metabolism</topic><topic>Cyclooxygenase 1 - metabolism</topic><topic>Cyclooxygenase 2 - metabolism</topic><topic>Cyclooxygenase 2 Inhibitors - administration & dosage</topic><topic>Cyclooxygenase 2 Inhibitors - blood</topic><topic>Cyclooxygenase 2 Inhibitors - pharmacokinetics</topic><topic>Cyclooxygenase 2 Inhibitors - pharmacology</topic><topic>Cyclooxygenase Inhibitors - administration & dosage</topic><topic>Cyclooxygenase Inhibitors - blood</topic><topic>Cyclooxygenase Inhibitors - pharmacokinetics</topic><topic>Cyclooxygenase Inhibitors - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>enzyme inhibition</topic><topic>enzyme inhibitors</topic><topic>Female</topic><topic>in vitro studies</topic><topic>Inhibitory Concentration 50</topic><topic>Injections, Intravenous - veterinary</topic><topic>Injections, Subcutaneous - veterinary</topic><topic>intravenous injection</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - blood</topic><topic>isozymes</topic><topic>Life Sciences</topic><topic>lipopolysaccharides</topic><topic>Male</topic><topic>nonsteroidal anti-inflammatory agents</topic><topic>pharmacokinetics</topic><topic>prostaglandin synthase</topic><topic>robenacoxib</topic><topic>subcutaneous injection</topic><topic>temporal variation</topic><topic>Thromboxane B2 - biosynthesis</topic><topic>Thromboxane B2 - blood</topic><topic>Thromboxane B2 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GIRAUDEL, J.M</creatorcontrib><creatorcontrib>TOUTAIN, P.-L</creatorcontrib><creatorcontrib>KING, J.N</creatorcontrib><creatorcontrib>LEES, P</creatorcontrib><collection>AGRIS</collection><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>Hyper Article en Ligne (HAL)</collection><jtitle>Journal of veterinary pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GIRAUDEL, J.M</au><au>TOUTAIN, P.-L</au><au>KING, J.N</au><au>LEES, P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib</atitle><jtitle>Journal of veterinary pharmacology and therapeutics</jtitle><addtitle>J Vet Pharmacol Ther</addtitle><date>2009-02</date><risdate>2009</risdate><volume>32</volume><issue>1</issue><spage>31</spage><epage>40</epage><pages>31-40</pages><issn>0140-7783</issn><eissn>1365-2885</eissn><abstract>Robenacoxib is a new nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration-time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX-1 and COX-2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B₂ provided a marker of both COX-1 and COX-2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC₅₀ were 28.9 (16.4-51.1) μ m (COX-1) and 0.058 (0.010-0.340) μ m (COX-2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX-1:COX-2) were 502.3 (IC₅₀/IC₅₀), 451.6 (IC₉₅/IC₉₅) and 17.05 (IC₂₀/IC₈₀). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX-1 and 90% inhibition of COX-2.</abstract><cop>Oxford, UK</cop><pub>Oxford, UK : Blackwell Publishing Ltd</pub><pmid>19161453</pmid><doi>10.1111/j.1365-2885.2008.01031.x</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0140-7783 |
| ispartof | Journal of veterinary pharmacology and therapeutics, 2009-02, Vol.32 (1), p.31-40 |
| issn | 0140-7783 1365-2885 |
| language | eng |
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| source | MEDLINE; Access via Wiley Online Library |
| subjects | Animals Anti-Inflammatory Agents, Non-Steroidal - administration & dosage Anti-Inflammatory Agents, Non-Steroidal - blood Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics Anti-Inflammatory Agents, Non-Steroidal - pharmacology Area Under Curve cats Cats - blood Cats - metabolism Cyclooxygenase 1 - metabolism Cyclooxygenase 2 - metabolism Cyclooxygenase 2 Inhibitors - administration & dosage Cyclooxygenase 2 Inhibitors - blood Cyclooxygenase 2 Inhibitors - pharmacokinetics Cyclooxygenase 2 Inhibitors - pharmacology Cyclooxygenase Inhibitors - administration & dosage Cyclooxygenase Inhibitors - blood Cyclooxygenase Inhibitors - pharmacokinetics Cyclooxygenase Inhibitors - pharmacology Dose-Response Relationship, Drug enzyme inhibition enzyme inhibitors Female in vitro studies Inhibitory Concentration 50 Injections, Intravenous - veterinary Injections, Subcutaneous - veterinary intravenous injection Isoenzymes - antagonists & inhibitors Isoenzymes - blood isozymes Life Sciences lipopolysaccharides Male nonsteroidal anti-inflammatory agents pharmacokinetics prostaglandin synthase robenacoxib subcutaneous injection temporal variation Thromboxane B2 - biosynthesis Thromboxane B2 - blood Thromboxane B2 - metabolism |
| title | Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib |
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