Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression.
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.
Cotten
Joseph F
JF
Harvard Medical School, Boston, Massachusetts, USA.
Husain
S Shaukat
SS
Forman
Stuart A
SA
Miller
Keith W
KW
Kelly
Elizabeth W
EW
Nguyen
Hieu H
HH
Raines
Douglas E
DE
D000303:Adrenal Cortex Diseases / Q000139:chemically induced*; D000305:Adrenal Cortex Hormones / Q000097:blood; D018686:Anesthetics, Intravenous / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004950:Esterases / Q000378:metabolism; D005045:Etomidate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007814:Larva; D008297:Male; D004856:Postural Balance / Q000187:drug effects; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D000305:Adrenal Cortex Hormones; D018686:Anesthetics, Intravenous; D011963:Receptors, GABA-A; C543057:methoxycarbonyletomidate; D004950:Esterases; D015742:Propofol; D005045:Etomidate