Methoxycarbonyl-etomidate: A Novel Rapidly Metabolized and Ultra-short-acting Etomidate Analogue that Does Not Produce Prolonged Adrenocortical Suppression. Export

@article{citeulike:5263822, abstract = {BACKGROUND:: 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. METHODS:: 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. RESULTS:: 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. CONCLUSIONS:: 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.}, author = {Cotten, Joseph F. and Husain, S. S. and Forman, Stuart A. and Miller, Keith W. and Kelly, Elizabeth W. and Nguyen, Hieu H. and Raines, Douglas E.}, citeulike-article-id = {5263822}, citeulike-linkout-0 = {http://dx.doi.org/10.1097/ALN.0b013e3181ae63d1}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19625798}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19625798}, doi = {10.1097/ALN.0b013e3181ae63d1}, issn = {1528-1175}, journal = {Anesthesiology}, month = {August}, number = {2}, pages = {240--249}, posted-at = {2009-07-25 20:00:40}, priority = {2}, title = {Methoxycarbonyl-etomidate: A Novel Rapidly Metabolized and Ultra-short-acting Etomidate Analogue that Does Not Produce Prolonged Adrenocortical Suppression.}, url = {http://dx.doi.org/10.1097/ALN.0b013e3181ae63d1}, volume = {111}, year = {2009} }

TY - JOUR ID - citeulike:5263822 L3 - citeulike-article-id:5263822 N2 - BACKGROUND:: 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. METHODS:: 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. RESULTS:: 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. CONCLUSIONS:: 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. IS - 2 JF - Anesthesiology SN - 1528-1175 EP - 249 TI - Methoxycarbonyl-etomidate: A Novel Rapidly Metabolized and Ultra-short-acting Etomidate Analogue that Does Not Produce Prolonged Adrenocortical Suppression. VL - 111 SP - 240 AU - Cotten, Joseph AU - Husain, SS AU - Forman, Stuart AU - Miller, Keith AU - Kelly, Elizabeth AU - Nguyen, Hieu AU - Raines, Douglas PY - 2009/08// UR - http://dx.doi.org/10.1097/ALN.0b013e3181ae63d1 ER -