The comparative pharmacodynamics of Remifentanil and its metabolite, GR90291, in a rat electroencephalographic model
The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model. Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time cours...
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| Veröffentlicht in: | Anesthesiology (Philadelphia) 1999-02, Vol.90 (2), p.535-544 |
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| creator | COX, E. H LANGEMEIJER, M. W. E GUBBENS-STIBBE, J. M MUIR, K. T DANHOF, M |
| description | The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model.
Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood.
Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6).
Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration. |
| doi_str_mv | 10.1097/00000542-199902000-00030 |
| format | Article |
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Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood.
Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6).
Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.</description><identifier>ISSN: 0003-3022</identifier><identifier>EISSN: 1528-1175</identifier><identifier>DOI: 10.1097/00000542-199902000-00030</identifier><identifier>PMID: 9952162</identifier><identifier>CODEN: ANESAV</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott</publisher><subject>Analgesics ; Analgesics, Opioid - administration & dosage ; Analgesics, Opioid - pharmacokinetics ; Anesthetics, Intravenous - administration & dosage ; Anesthetics, Intravenous - pharmacokinetics ; Animals ; Biological and medical sciences ; Brain - metabolism ; Brain - physiopathology ; Drug Interactions ; Infusions, Intravenous ; Male ; Medical sciences ; Neuropharmacology ; Pharmacology. Drug treatments ; Piperidines - administration & dosage ; Piperidines - pharmacokinetics ; Rats ; Rats, Wistar ; Remifentanil</subject><ispartof>Anesthesiology (Philadelphia), 1999-02, Vol.90 (2), p.535-544</ispartof><rights>1999 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-3158b461541432853b863dcac738b34e392035ab39a86d5ca92c7d58aeed8e933</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1687523$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9952162$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>COX, E. H</creatorcontrib><creatorcontrib>LANGEMEIJER, M. W. E</creatorcontrib><creatorcontrib>GUBBENS-STIBBE, J. M</creatorcontrib><creatorcontrib>MUIR, K. T</creatorcontrib><creatorcontrib>DANHOF, M</creatorcontrib><title>The comparative pharmacodynamics of Remifentanil and its metabolite, GR90291, in a rat electroencephalographic model</title><title>Anesthesiology (Philadelphia)</title><addtitle>Anesthesiology</addtitle><description>The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model.
Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood.
Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6).
Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.</description><subject>Analgesics</subject><subject>Analgesics, Opioid - administration & dosage</subject><subject>Analgesics, Opioid - pharmacokinetics</subject><subject>Anesthetics, Intravenous - administration & dosage</subject><subject>Anesthetics, Intravenous - pharmacokinetics</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Brain - metabolism</subject><subject>Brain - physiopathology</subject><subject>Drug Interactions</subject><subject>Infusions, Intravenous</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperidines - administration & dosage</subject><subject>Piperidines - pharmacokinetics</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Remifentanil</subject><issn>0003-3022</issn><issn>1528-1175</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkN1KAzEQhYMotVYfQciFl13dJJvd5FKKVqEglHq9zCazNrJ_JKvQtze1tQ4Mw5nhHIaPEMrSe5bq4iHdl8x4wrTWKY8iiS3SMzJlkquEsUKek-l-l4iU80tyFcJnlIUUakImWkvOcj4l42aL1PTtAB5G94102IJvwfR210HrTKB9TdfYuhq7ETrXUOgsdWOgLY5Q9Y0bcU6X6_iEZnPqOgo0JlFs0Iy-x85gTGz6Dw_D1hna9haba3JRQxPw5jhn5P35abN4SVZvy9fF4yoxmZRjIphUVZYzmbFMcCVFpXJhDZhCqEpkKDRPhYRKaFC5lQY0N4WVChCtQi3EjKhDrvF9CB7rcvCuBb8rWVruOZZ_HMsTx_KXY7TeHqzDV9WiPRmP4OL97niHYKCpPXTGhf_8XBWSC_EDzOZ6lQ</recordid><startdate>19990201</startdate><enddate>19990201</enddate><creator>COX, E. H</creator><creator>LANGEMEIJER, M. W. E</creator><creator>GUBBENS-STIBBE, J. M</creator><creator>MUIR, K. T</creator><creator>DANHOF, M</creator><general>Lippincott</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></search><sort><creationdate>19990201</creationdate><title>The comparative pharmacodynamics of Remifentanil and its metabolite, GR90291, in a rat electroencephalographic model</title><author>COX, E. H ; LANGEMEIJER, M. W. E ; GUBBENS-STIBBE, J. M ; MUIR, K. T ; DANHOF, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-3158b461541432853b863dcac738b34e392035ab39a86d5ca92c7d58aeed8e933</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Analgesics</topic><topic>Analgesics, Opioid - administration & dosage</topic><topic>Analgesics, Opioid - pharmacokinetics</topic><topic>Anesthetics, Intravenous - administration & dosage</topic><topic>Anesthetics, Intravenous - pharmacokinetics</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Brain - metabolism</topic><topic>Brain - physiopathology</topic><topic>Drug Interactions</topic><topic>Infusions, Intravenous</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperidines - administration & dosage</topic><topic>Piperidines - pharmacokinetics</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Remifentanil</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>COX, E. H</creatorcontrib><creatorcontrib>LANGEMEIJER, M. W. E</creatorcontrib><creatorcontrib>GUBBENS-STIBBE, J. M</creatorcontrib><creatorcontrib>MUIR, K. T</creatorcontrib><creatorcontrib>DANHOF, M</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><jtitle>Anesthesiology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>COX, E. H</au><au>LANGEMEIJER, M. W. E</au><au>GUBBENS-STIBBE, J. M</au><au>MUIR, K. T</au><au>DANHOF, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The comparative pharmacodynamics of Remifentanil and its metabolite, GR90291, in a rat electroencephalographic model</atitle><jtitle>Anesthesiology (Philadelphia)</jtitle><addtitle>Anesthesiology</addtitle><date>1999-02-01</date><risdate>1999</risdate><volume>90</volume><issue>2</issue><spage>535</spage><epage>544</epage><pages>535-544</pages><issn>0003-3022</issn><eissn>1528-1175</eissn><coden>ANESAV</coden><abstract>The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model.
Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood.
Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6).
Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott</pub><pmid>9952162</pmid><doi>10.1097/00000542-199902000-00030</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Analgesics Analgesics, Opioid - administration & dosage Analgesics, Opioid - pharmacokinetics Anesthetics, Intravenous - administration & dosage Anesthetics, Intravenous - pharmacokinetics Animals Biological and medical sciences Brain - metabolism Brain - physiopathology Drug Interactions Infusions, Intravenous Male Medical sciences Neuropharmacology Pharmacology. Drug treatments Piperidines - administration & dosage Piperidines - pharmacokinetics Rats Rats, Wistar Remifentanil |
| title | The comparative pharmacodynamics of Remifentanil and its metabolite, GR90291, in a rat electroencephalographic model |
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