Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression

• Published in: Anesthesiology (Philadelphia) 2009-08, Vol.111 (2), p.240-249
• Main Authors: Cotten, Joseph F, Husain, S Shaukat, Forman, Stuart A, Miller, Keith W, Kelly, Elizabeth W, Nguyen, Hieu H, Raines, Douglas E
• Format: Article
• Language: English
• 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
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0b013e3181ae63d1

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.