Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression
Etomidate is a rapidly acting sedative-hypnotic that provides hemodynamic stability. It causes prolonged suppression of adrenocortical steroid synthesis; therefore, its clinical utility and safety are limited. The authors describe the results of studies to define the pharmacology of (R)-3-methoxy-3-...
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| Veröffentlicht in: | Anesthesiology (Philadelphia) 2009-08, Vol.111 (2), p.240-249 |
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| creator | Cotten, Joseph F Husain, S Shaukat Forman, Stuart A Miller, Keith W Kelly, Elizabeth W Nguyen, Hieu H Raines, Douglas E |
| description | Etomidate is a rapidly acting sedative-hypnotic that provides hemodynamic stability. It causes prolonged suppression of adrenocortical steroid synthesis; therefore, its clinical utility and safety are limited. The authors describe the results of studies to define the pharmacology of (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), the first etomidate analogue designed to be susceptible to ultra-rapid metabolism.
The gamma-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared by using electrophysiological techniques in human alpha1beta2gamma2l receptors. MOC-etomidate's hypnotic concentration was determined in tadpoles by using a loss of righting reflex assay. Its in vitro metabolic half-life was measured in human liver S9 fraction, and the resulting metabolite was provisionally identified by using high-performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats.
MOC-etomidate potently enhanced gamma-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order, with an in vitro half-life of 4.4 min versus more than 40 min for etomidate. MOC-etomidate's only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 min after administration.
MOC-etomidate is an etomidate analogue that retains etomidate's important favorable pharmacological properties. However, it is rapidly metabolized, ultra-short-acting, and does not produce prolonged adrenocortical suppression after bolus administration. |
| doi_str_mv | 10.1097/ALN.0b013e3181ae63d1 |
| format | Article |
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The gamma-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared by using electrophysiological techniques in human alpha1beta2gamma2l receptors. MOC-etomidate's hypnotic concentration was determined in tadpoles by using a loss of righting reflex assay. Its in vitro metabolic half-life was measured in human liver S9 fraction, and the resulting metabolite was provisionally identified by using high-performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats.
MOC-etomidate potently enhanced gamma-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order, with an in vitro half-life of 4.4 min versus more than 40 min for etomidate. MOC-etomidate's only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 min after administration.
MOC-etomidate is an etomidate analogue that retains etomidate's important favorable pharmacological properties. However, it is rapidly metabolized, ultra-short-acting, and does not produce prolonged adrenocortical suppression after bolus administration.</description><identifier>ISSN: 0003-3022</identifier><identifier>EISSN: 1528-1175</identifier><identifier>DOI: 10.1097/ALN.0b013e3181ae63d1</identifier><identifier>PMID: 19625798</identifier><language>eng</language><publisher>United States</publisher><subject>Adrenal Cortex Diseases - chemically induced ; Adrenal Cortex Hormones - blood ; Anesthetics, Intravenous - adverse effects ; Anesthetics, Intravenous - pharmacology ; Animals ; Biotransformation ; Dose-Response Relationship, Drug ; Electrophysiology ; Esterases - metabolism ; Etomidate - adverse effects ; Etomidate - analogs & derivatives ; Etomidate - pharmacology ; Half-Life ; Hemodynamics - drug effects ; Humans ; In Vitro Techniques ; Larva ; Male ; Postural Balance - drug effects ; Propofol - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-A - drug effects ; Structure-Activity Relationship ; Xenopus laevis</subject><ispartof>Anesthesiology (Philadelphia), 2009-08, Vol.111 (2), p.240-249</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19625798$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cotten, Joseph F</creatorcontrib><creatorcontrib>Husain, S Shaukat</creatorcontrib><creatorcontrib>Forman, Stuart A</creatorcontrib><creatorcontrib>Miller, Keith W</creatorcontrib><creatorcontrib>Kelly, Elizabeth W</creatorcontrib><creatorcontrib>Nguyen, Hieu H</creatorcontrib><creatorcontrib>Raines, Douglas E</creatorcontrib><title>Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression</title><title>Anesthesiology (Philadelphia)</title><addtitle>Anesthesiology</addtitle><description>Etomidate is a rapidly acting sedative-hypnotic that provides hemodynamic stability. It causes prolonged suppression of adrenocortical steroid synthesis; therefore, its clinical utility and safety are limited. The authors describe the results of studies to define the pharmacology of (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), the first etomidate analogue designed to be susceptible to ultra-rapid metabolism.
The gamma-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared by using electrophysiological techniques in human alpha1beta2gamma2l receptors. MOC-etomidate's hypnotic concentration was determined in tadpoles by using a loss of righting reflex assay. Its in vitro metabolic half-life was measured in human liver S9 fraction, and the resulting metabolite was provisionally identified by using high-performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats.
MOC-etomidate potently enhanced gamma-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order, with an in vitro half-life of 4.4 min versus more than 40 min for etomidate. MOC-etomidate's only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 min after administration.
MOC-etomidate is an etomidate analogue that retains etomidate's important favorable pharmacological properties. However, it is rapidly metabolized, ultra-short-acting, and does not produce prolonged adrenocortical suppression after bolus administration.</description><subject>Adrenal Cortex Diseases - chemically induced</subject><subject>Adrenal Cortex Hormones - blood</subject><subject>Anesthetics, Intravenous - adverse effects</subject><subject>Anesthetics, Intravenous - pharmacology</subject><subject>Animals</subject><subject>Biotransformation</subject><subject>Dose-Response Relationship, Drug</subject><subject>Electrophysiology</subject><subject>Esterases - metabolism</subject><subject>Etomidate - adverse effects</subject><subject>Etomidate - analogs & derivatives</subject><subject>Etomidate - pharmacology</subject><subject>Half-Life</subject><subject>Hemodynamics - drug effects</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Larva</subject><subject>Male</subject><subject>Postural Balance - drug effects</subject><subject>Propofol - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, GABA-A - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>Xenopus laevis</subject><issn>0003-3022</issn><issn>1528-1175</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkcFq3DAQhkVoabZJ3yAUvYATybItK4dCCGlT2LaX5mxG0nhXRSsZSQ7Zvkpetl4S0qanYZj5vmH4CTnj7JwzJS-u1t_PmWZcoOA9B-yE5Udkxdu6rziX7RuyYoyJSrC6Pibvc_61tLIV_TtyzFVXt1L1K_L4Dcs2PuwNJB3D3ldY4s5ZKHhJgYZ4j54mmJz1e7rDAjp69xsthWDp7EuCKm9jKhWY4sKGvtDLAvi4mZGWLRRqI-bFVuiUop0NHqqPYXMw2YQhmkXiDHia52lKmLOL4ZS8HcFn_PBcT8jd55uf17fV-seXr9dX68oIpkrVCCbQamubFphVXGvsuWy6pmcdSrBjzXQjajRWouk6qRX0tWIwjmZUXEhxQj49eadZ79AaDMtffpiS20HaDxHc8HoS3HbYxPuhlkI1nC-C5klgUsw54fjCcjYcwhqWsIb_w1qwj__e_Qs9pyP-ANWTmTE</recordid><startdate>20090801</startdate><enddate>20090801</enddate><creator>Cotten, Joseph F</creator><creator>Husain, S Shaukat</creator><creator>Forman, Stuart A</creator><creator>Miller, Keith W</creator><creator>Kelly, Elizabeth W</creator><creator>Nguyen, Hieu H</creator><creator>Raines, Douglas E</creator><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>5PM</scope></search><sort><creationdate>20090801</creationdate><title>Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression</title><author>Cotten, Joseph F ; Husain, S Shaukat ; Forman, Stuart A ; Miller, Keith W ; Kelly, Elizabeth W ; Nguyen, Hieu H ; Raines, Douglas E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c309t-4303edbdd45a0d91bbe817464806e7adf20b432ecd7ec667b9a8290affcf91373</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adrenal Cortex Diseases - chemically induced</topic><topic>Adrenal Cortex Hormones - blood</topic><topic>Anesthetics, Intravenous - adverse effects</topic><topic>Anesthetics, Intravenous - pharmacology</topic><topic>Animals</topic><topic>Biotransformation</topic><topic>Dose-Response Relationship, Drug</topic><topic>Electrophysiology</topic><topic>Esterases - metabolism</topic><topic>Etomidate - adverse effects</topic><topic>Etomidate - analogs & derivatives</topic><topic>Etomidate - pharmacology</topic><topic>Half-Life</topic><topic>Hemodynamics - drug effects</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Larva</topic><topic>Male</topic><topic>Postural Balance - drug effects</topic><topic>Propofol - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, GABA-A - drug effects</topic><topic>Structure-Activity Relationship</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cotten, Joseph F</creatorcontrib><creatorcontrib>Husain, S Shaukat</creatorcontrib><creatorcontrib>Forman, Stuart A</creatorcontrib><creatorcontrib>Miller, Keith W</creatorcontrib><creatorcontrib>Kelly, Elizabeth W</creatorcontrib><creatorcontrib>Nguyen, Hieu H</creatorcontrib><creatorcontrib>Raines, Douglas E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Anesthesiology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cotten, Joseph F</au><au>Husain, S Shaukat</au><au>Forman, Stuart A</au><au>Miller, Keith W</au><au>Kelly, Elizabeth W</au><au>Nguyen, Hieu H</au><au>Raines, Douglas E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression</atitle><jtitle>Anesthesiology (Philadelphia)</jtitle><addtitle>Anesthesiology</addtitle><date>2009-08-01</date><risdate>2009</risdate><volume>111</volume><issue>2</issue><spage>240</spage><epage>249</epage><pages>240-249</pages><issn>0003-3022</issn><eissn>1528-1175</eissn><abstract>Etomidate is a rapidly acting sedative-hypnotic that provides hemodynamic stability. It causes prolonged suppression of adrenocortical steroid synthesis; therefore, its clinical utility and safety are limited. The authors describe the results of studies to define the pharmacology of (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), the first etomidate analogue designed to be susceptible to ultra-rapid metabolism.
The gamma-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared by using electrophysiological techniques in human alpha1beta2gamma2l receptors. MOC-etomidate's hypnotic concentration was determined in tadpoles by using a loss of righting reflex assay. Its in vitro metabolic half-life was measured in human liver S9 fraction, and the resulting metabolite was provisionally identified by using high-performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats.
MOC-etomidate potently enhanced gamma-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order, with an in vitro half-life of 4.4 min versus more than 40 min for etomidate. MOC-etomidate's only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 min after administration.
MOC-etomidate is an etomidate analogue that retains etomidate's important favorable pharmacological properties. However, it is rapidly metabolized, ultra-short-acting, and does not produce prolonged adrenocortical suppression after bolus administration.</abstract><cop>United States</cop><pmid>19625798</pmid><doi>10.1097/ALN.0b013e3181ae63d1</doi><tpages>10</tpages></addata></record> |
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| ispartof | Anesthesiology (Philadelphia), 2009-08, Vol.111 (2), p.240-249 |
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| subjects | Adrenal Cortex Diseases - chemically induced Adrenal Cortex Hormones - blood Anesthetics, Intravenous - adverse effects Anesthetics, Intravenous - pharmacology Animals Biotransformation Dose-Response Relationship, Drug Electrophysiology Esterases - metabolism Etomidate - adverse effects Etomidate - analogs & derivatives Etomidate - pharmacology Half-Life Hemodynamics - drug effects Humans In Vitro Techniques Larva Male Postural Balance - drug effects Propofol - pharmacology Rats Rats, Sprague-Dawley Receptors, GABA-A - drug effects Structure-Activity Relationship Xenopus laevis |
| title | Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression |
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