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

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.

Figure 1

(A) Synthesis of methoxycarbonyl-etomidate (MOC-etomidate). (B) Structure of etomidate.

Figure 2

Methoxycarbonyl-etomidate (MOC-etomidate) concentration response curve for loss of righting reflex (LORR) in tadpoles. Each data point represents the results from a single tadpole. The curve is a fit of the data set yielding an EC50 of 8 ± 2 μM. All tadpoles recovered when removed from methoxycarbonyl-etomidate and returned to fresh water.

Figure 3

Methoxycarbonyl-etomidate (MOC-etomidate) and etomidate modulation of human α₁β₂γ_2Lγ-aminobutyric acid type A receptor function. (A) Representative traces showing enhancement of currents evoked by EC_5–10γ-aminobutyric acid (GABA) by methoxycarbonyl-etomidate and etomidate. (B) GABA concentration-response curves for peak current activation in the absence (control) or presence of either methoxycarbonyl-etomidate or etomidate. Error bars indicate the SD. Both drugs shifted the GABA concentration-response curves leftward, reducing the GABA EC₅₀ from 12.7 ± 0.4 μM in the absence of drug to 3.3 ± 0.1 μM and 1.6 ± 0.1 μM in the presence of 8 μM methoxycarbonyl-etomidate and 2 μM etomidate, respectively (n = 3 for each data point).

Figure 4

Metabolic stability of methoxycarbonyl-etomidate (MOC-etomidate) vs. etomidate in pooled human liver S9 fraction. The metabolic half-life of methoxycarbonyl-etomidate was approximately 4.4 min. There was no detectable metabolism of etomidate during the 40 min incubation period.

Figure 5

Methoxycarbonyl-etomidate (MOC-etomidate) metabolite identification. (A) Mass spectrometry spectra of the major metabolite (main spectrum; m/z 289.2) and its major fragment ion (left inset spectrum; m/z 185.2). The metabolite produced a single major fragment ion at m/z 185.2 with a neutral loss of m/z 104, consistent with a conserved region of the parent compound. Subsequent mass spectrometry/mass spectrometry analysis of m/z 185.2 produced 3 major ions at m/z 94.96, 113.11, and 166.98. Right inset shows a possible fragmentation pathway supporting the proposed metabolite structure. (B) Metabolic pathway for methoxycarbonyl-etomidate upon incubation with human liver S9 fraction based on analysis of the metabolite’s major fragment ion.

Figure 6

Dose-response curves for loss of righting reflex (LORR) and duration of loss of righting reflex in rats. Each data point represents the results from a single rat. (A) Etomidate, propofol, and methoxycarbonyl-etomidate (MOC-etomidate) produced loss of righting reflex with ED50s of 1.00 ± 0.03 mg/kg, 4.1 ± 0.3 mg/kg, and 5.2 ± 1 mg/kg, respectively. (B) For all three drugs, the duration of loss of righting reflex increased linearly with the logarithm of the dose. The slope of this relationship was 27 ± 7, 22 ± 4, and 2.8 ± 0.4 for etomidate, propofol, and methoxycarbonyl-etomidate, respectively.

Figure 7

The effects of methoxycarbonyl-etomidate (MOC-etomidate), propofol, and etomidate on mean blood pressure in rats. Drugs were given at doses equal to twice their respective ED50s for loss of righting reflex. Drug was injected at time 0. Each data point represents the average (± SD) change in mean blood pressure from 3 rats during each 30 s epoch. The inset shows a representative arterial blood pressure trace prior to drug administration.

Figure 8

Adrenocorticotropic hormone_1–24-stimulated serum corticosterone concentrations in rats 30 min following administration of vehicle, etomidate, or methoxycarbonyl-etomidate (MOC-etomidate). Drugs were given at doses equal to twice their respective ED50s for loss of righting reflex. Four rats were studied in each group. Average serum corticosterone concentrations (± SD) were 740 ±125 ng/ml, 320 ± 97 ng/ml, and 750 ± 58 ng/ml following administration of vehicle, etomidate, and methoxycarbonyl-etomidate, respectively. *, P < 0.05, N.S., no significant difference.